key: cord-0002642-qwnb9x57
authors: Tien, Wei-Sheng; Chen, Jun-Hong; Wu, Kun-Pin
title: SheddomeDB: the ectodomain shedding database for membrane-bound shed markers
date: 2017-03-14
journal: BMC Bioinformatics
DOI: 10.1186/s12859-017-1465-7
sha: b9f063ab66715b75706b11ab3b0a2af52294cd5b
doc_id: 2642
cord_uid: qwnb9x57

BACKGROUND: A number of membrane-anchored proteins are known to be released from cell surface via ectodomain shedding. The cleavage and release of membrane proteins has been shown to modulate various cellular processes and disease pathologies. Numerous studies revealed that cell membrane molecules of diverse functional groups are subjected to proteolytic cleavage, and the released soluble form of proteins may modulate various signaling processes. Therefore, in addition to the secreted protein markers that undergo secretion through the secretory pathway, the shed membrane proteins may comprise an additional resource of noninvasive and accessible biomarkers. In this context, identifying the membrane-bound proteins that will be shed has become important in the discovery of clinically noninvasive biomarkers. Nevertheless, a data repository for biological and clinical researchers to review the shedding information, which is experimentally validated, for membrane-bound protein shed markers is still lacking. RESULTS: In this study, the database SheddomeDB was developed to integrate publicly available data of the shed membrane proteins. A comprehensive literature survey was performed to collect the membrane proteins that were verified to be cleaved or released in the supernatant by immunological-based validation experiments. From 436 studies on shedding, 401 validated shed membrane proteins were included, among which 199 shed membrane proteins have not been annotated or validated yet by existing cleavage databases. SheddomeDB attempted to provide a comprehensive shedding report, including the regulation of shedding machinery and the related function or diseases involved in the shedding events. In addition, our published tool ShedP was embedded into SheddomeDB to support researchers for predicting the shedding event on unknown or unrecorded membrane proteins. CONCLUSIONS: To the best of our knowledge, SheddomeDB is the first database for the identification of experimentally validated shed membrane proteins and currently may provide the most number of membrane proteins for reviewing the shedding information. The database included membrane-bound shed markers associated with numerous cellular processes and diseases, and some of these markers are potential novel markers because they are not annotated or validated yet in other databases. SheddomeDB may provide a useful resource for discovering membrane-bound shed markers. The interactive web of SheddomeDB is publicly available at http://bal.ym.edu.tw/SheddomeDB/. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-017-1465-7) contains supplementary material, which is available to authorized users.

A large class of proteins is known to be secreted from the cell to the extracellular space. The secreted proteins such as hormones, enzymes, and antibodies play vital regulatory roles in biological signaling and may serve as clinically noninvasive biomarkers and potential therapeutic targets [1, 2] . In addition to the proteins that undergo protein secretion via secretory pathways, membrane proteins are known to be released into the extracellular milieu via ectodomain shedding. Certain membrane-bound proteins, including cell adhesion molecules, growth factors, cytokines, and cell receptors, can be proteolytically cleaved by sheddase that results in the release of soluble forms of fragments. The process of ectodomain shedding has been shown to regulate various pathologies and diseases such as degeneration, inflammation, and cancer and physiological processes such as proliferation, differentiation, and migration [3, 4] . In this context, the cleaved and released membrane proteins resulting from shedding events may comprise additional resources of valuable secreted and soluble biomarkers for pathological states or physiological conditions.

Previous studies on membrane proteins revealed that only about 2 or 4% of cell surface molecules undergo the shedding process [5, 6] ; hence, it is apparent that not every membrane protein will be released through proteolytic shedding. Therefore, to assess whether a membranebound protein will be released from cells and to identify membrane-bound shed markers that are of clinical potential, a data repository dedicated to provide shedding information that is experimentally validated for membrane proteins seems indispensable. Although cleavage databases such as MEROPS [7] , PMAP-SubstrateDB [8] , and HPRD [9] have been developed as information resources for proteases, substrates, and cleavage events, a portion of cleavage records collected by the databases may be based on library-based approaches for identification of protease cleavage sites [10, 11] , and the putative substrates identified in the original literature may not be validated or physiologically relevant. In addition, currently, some shed membrane proteins that were identified by shedding studies may not have yet been recorded and annotated in these cleavage databases.

In this context, the database SheddomeDB was designed for the identification of shed membrane proteins that are released through proteolytic cleavage. The membrane proteins that were verified to be cleaved or released in the supernatant by immunological-based validation experiments were included in our database. Based on a comprehensive literature survey on shedding event studies, a total of 401 validated shed membrane proteins were identified, among which 199 shed membrane proteins have not been annotated or validated yet by current cleavage databases. SheddomeDB also provides a user-friendly web interface for researchers to search or browse proteins of interest. For each experimentally validated shed membrane protein, SheddomeDB attempted to provide a comprehensive shedding report based on literature references, including the regulation of shedding machinery and the related function or diseases involved in the shedding events. The cross-references to other resources, such as the released evidence in secretome data and the existing records of protease cleavage sites, were provided in SheddomeDB as well. In addition, the previously published prediction tool ShedP [12] was embedded into SheddomeDB. ShedP is a computational method developed to predict the shedding event on membrane proteins based on the protein sequence. By incorporating a prediction web interface for ShedP, SheddomeDB also supports the researchers for the assessment of shedding events on the unknown or unrecorded membrane proteins.

Thus, by collecting experimentally validated shed membrane proteins from literature references, SheddomeDB may provide a useful resource of membrane-bound shed markers associated with numerous cellular processes and diseases, including some potential novel markers that are not annotated or validated yet in other databases. Sheddo-meDB may be a useful bioinformatics design in sheddome marker discovery and to help investigate the regulatory role of membrane proteins in physiological and pathological processes. SheddomeDB is publicly available at http://bal.ym.edu.tw/SheddomeDB/.

The MYSQL relational database version 5.0.45 (http:// www.mysql.com) was used in the current study to design and construct the SheddomeDB database and the interactive web interface. A JAVA-based model-view-controller (MVC) framework was utilized for the web interface to separate the logic, application, and the presentation into three distinct layers. All the interactions between the web client requests and the server side were handled by Apache web server. The dynamic web pages were designed using JavaServer Pages (JSP) and Cascading Style Sheets (CSS), and the user-interactive pages were supported by JavaScript and its library jQuery for client-side scripting.

A comprehensive literature survey was conducted to identify the membrane proteins that were experimentally validated to be cleaved or released into the supernatant. By searching the PubMed database using the following keywords: "shedding", "proteolytic", "cleavage", "protease", "soluble form" and "released" the relevant studies on membrane protein shedding or protease cleavage were first acquired. We further manually reviewed the published studies and screened for the validated shed membrane proteins based on the following selection criteria: (1) The membrane proteins were verified to be cleaved by protease and protease inhibitors or the release of the soluble forms of proteins was detected in the culture supernatant. (2) The shedding events of membrane proteins were validated by antibody-based probes against the endogenous protein or against stably expressed genes encoding the protein. The curated publications that met the screening criteria were further selected as the data source to collect all the relevant data on membrane protein shedding. We mapped the membrane proteins in each curated publication to the UniProtKB/Swiss-Prot database [13] to uniform the protein ID based on the protein name and the organism source of the protein. In addition, because the functional consequences of membrane protein shedding can be diverse and depend on the protein function or the shed form of fragments, we grouped each shed membrane protein into functional categories based on the regulated functions or diseases suggested in the shedding literature. If the functional consequences of protein shedding were not clarified in the original studies, the shed membrane protein was then categorized based on the function description or annotation in the UniProtKB/Swiss-Prot database.

The in-house prediction tool ShedP previously developed to predict shedding events of membrane proteins was incorporated into the SheddomeDB database. ShedP is a support vector machine (SVM)-based model [14] built by supervised machine learning that discriminates between shed membrane proteins and nonshed membrane proteins. The SVM model based on PseAAC [15] feature representation was constructed as our ShedP tool after a 5-fold cross-validation training procedure. At present, ShedP is the computational method published to predict shedding events of membrane proteins. To support the researchers for assessing the likelihood of an unknown or unrecorded membrane protein to be cleaved and released from the cell, we have also integrated a web interface to the prediction by ShedP into the Sheddo-meDB database, enabling valuable hints to be gained by in silico prediction.

In the present study, 436 curated studies were selected based on our literature survey process [3, , and a total of 401 validated shed membrane proteins were collected. Among the shed membrane proteins included in SheddomeDB, 22 proteins have not yet been annotated by existing cleavage databases MEROPS, PMAP-SubstrateDB, and HPRD. In addition, among those identified membrane proteins that have already been recorded in cleavage databases, 28 membrane proteins were only shown to undergo cleavage by signal peptidase [451] [452] [453] [454] [455] [456] [457] [458] [459] [460] [461] [462] and 149 membrane proteins were only referenced by one substrate specificity study using a computational prediction model [463] . The cleavage records of membrane proteins in these studies may be neither relevant to membrane protein shedding nor experimentally validated. Therefore, our results revealed that a total of 199 shed membrane proteins in SheddomeDB were not annotated or validated yet by other cleavage databases. The details of the identified shed membrane proteins and the reference studies are summarized in (Additional file 1: Table S1 ).

Because the process of proteolytic shedding has been shown to be involved in various physiological processes and diseases, it is of importance to know which biological function categories or diseases may be regulated or related to the shedding of membrane proteins. Thus, we further grouped the validated shed membrane proteins into function categories manually based on the functional consequences referenced by shedding studies or functional description in the UniProtKB/Swiss-Prot database. First, the shed membrane proteins were grouped into the category "disease" if the proteins were shown to be involved in the disease progression or suggested as disease marker candidates. For instance, the shedding events of the proteins CDH1, EFNA1, and SDC1 were suggested to be involved in cancer invasion and immune escape [16] [17] [18] [19] [20] ; the shedding events of SNCA and APP were shown to be involved in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease [21] [22] [23] ; the shedding event of NRP2 was involved in immune disorders such as rheumatoid arthritis [24] ; that of SDC4 was suggested to be involved in cardiovascular diseases such as atrial fibrillation [25] ; HAVCR2 shedding event being implicated in HIV infection [26] ; and the shedding event of CADM1 was shown to be involved in diabetes [27, 28] . In addition, several shed or soluble membrane proteins were suggested to be marker candidates for cancers (e.g., PVRL4 [29] , CD200 [30, 31] , CDH17 [32] ), atherosclerosis (e.g., SORL1 [33] [34] [35] [36] ), diabetes mellitus (e.g., CLEC1B [37] ), neurodegenerative disorders (e.g., PDGFRB [38, 39] ), and hepatocyte damage (e.g., PTPRG [40] ).

Then, a large portion of the shed membrane proteins were found to be related to immune response or neural signaling and were categorized into "immune and inflammation" or "central nervous system," respectively. For instance, the shedding of numerous cytokines, cell receptors, and cell adhesion molecules was shown to be involved in leukocyte recruitment (e.g., CXCL16 [23, 41, 42] , CDH5 [23, 41] , TNFRSF8 [41, 43] ), T-cell proliferation (e.g., Lag3 [41, 44] ), and other immunological modulations (e.g., CR2 [45] ). In contrast, the shedding of cell adhesion molecules, ligands, and cell receptors was involved in axon guidance (e.g., Epha4 [46] , Neo1 [47] ) and neurite outgrowth (e.g., NCAM1 [48] [49] [50] ). In addition, another group of shed membrane proteins were found to be specifically related to the cardiovascular system and were further categorized into "angiogenesis" or "blood and homoeostasis." For instance, the shedding of the proteins JAM3 and CLEC14A was suggested to be involved in the regulation of angiogenesis [51, 52] , and the shedding of the proteins GP1BA and GP5 was suggested to be involved in the regulation of platelet hemostasis [23, 53] .

For the remaining shed membrane proteins, most of the growth factors (e.g., BTC [23, 54, 55] ), growth factor receptors (e.g., NGFR [56, 57] ), morphogens (e.g., SHH [58] ), and cell adhesion molecules (e.g., EPCAM [59, 60] ) were shown to be involved in cell proliferation, migration, and morphogenesis and were categorized into "cell growth and development." In addition, some shed proteins were found to be related to metabolism and were grouped into "lipid" (e.g., DLK1 [61, 62] ), "melanogenesis" (e.g., PMEL [63] ), "insulin" (e.g., TMEM27 [64, 65] ), and "renal" (e.g., UMOD [66] ). In addition, others were found to be related to protein function and were grouped into "enzyme" (e.g., ACE [67] ), "transporter" (e.g., FOLR1 [68] ), and "cell surface structure" (e.g., DSG2 [69] ). Finally, we found some proteins that were specifically related to "aging" (e.g., KL [70, 71] ). Thus, as depicted in Fig. 1 , the 401 identified shed membrane proteins were grouped into 14 categories; the details of the protein members in each function category are summarized in (Additional file 1: Table S2 ) and can be reviewed in our browsed pages.

SheddomeDB provided a user-friendly web interface for researchers to search or browse proteins of interest. To query the database, the researchers can begin the search task from the "Search" page in which two query options were provided (Fig. 2) . First, the database can be queried by directly specifying the protein UniProt ID. In contrast, the researchers can make a text similarity query by inputting the protein name or gene symbol and specify the desired one from all possible protein candidates in the interactive page. In addition, the researchers can choose the "Browse" page to browse the membrane proteins based on function categories (the disease or function categories involved in or related to shedding process) (Fig. 2) . In the results pages for each experimentally validated shed membrane protein, a comprehensive shedding report was provided by SheddomeDB in four sections (Fig. 3) , as follows: (i) In section A, the basic information such as protein name, gene symbol, organism, and extracellular region were referenced from the UniProtKB/ Swiss-Prot database. In addition, the membrane protein type annotated from UniProtKB/Swiss-Prot was also provided to show whether the membrane protein is (1.) lipid or GPI-anchored, (2.) topological (with extracellular and transmembrane domain, (3.) cell membrane annotated (annotated localized in cell membranes), and (4) other membrane proteins (proteins annotated at other subcellular localizations). (ii) The cross-references to the secretome released information were revealed in section B. If the query proteins were annotated to be released by secretome studies [72] [73] [74] [464] [465] [466] or by the secreted protein datasets in the databases the secretome databases HCSD [467] and Sys-BodyFluid [468] , the secreted protein database SPD [469] , and the subcellular localization database LOCATE [470] , the secretome information such as the secretome database, secreted cell type, the reference PubMed ID, and the protein ID used in the reference literature will be summarized and provided. (iii) In section C, the regulation of the shedding machinery, the related function or disease, the protease name, and the PubMed ID of the shedding reference were summarized. (iv) In section D, the cross-references to existing cleavage sites records from current cleavage databases MEROPS, PMAP-SubstrateDB, and HPRD were provided. The cleavage information such as the cleavage database, protease name, reference PubMed ID, the cut location, and the cut sequence motif were provided. In addition, the protein sequence structure was represented in which the extracellular domain region and the protease cleavage site can be visualized.

SheddomeDB incorporated a web interface to prediction by ShedP so as to gain valuable hints by in silico prediction. By inserting the protein sequence of a queried protein, the users can assess the likelihood of an unknown or unrecorded membrane protein to be cleaved and released from the cell. Based on the prediction model, a query protein whose predicted probability was greater than or equal to 0.5 was regarded as positive and predicted to be shed, otherwise it was predicted as negative and nonshed (Fig. 4 ).

As more and more studies have revealed the regulatory role of ectodomain shedding in various cellular processes and pathologies, the identification of shed and released membrane proteins is becoming important in the field of biomarker discovery and sheddome proteomics. To determine and assess the possible membrane protein candidates undergoing shedding and released from the cells, the database SheddomeDB is the first sheddome-based database developed to store and query publicly available data on shed membrane proteins. For each queried membrane protein, SheddomeDB provides the researchers comprehensive cross-references including the released evidence in the secretome, protease cleavage record, and biologically validated shedding report. Thus, the bioinformatics-based database Shed-domeDB may serve as a useful resource for membranebound secreted markers. For each query membrane protein, the information was provided in four sections in the result pages. Section A revealed the basic protein information from UniProtKB/Swiss-Prot. Section B provided secretome released information. Section C summarized the biological information from the biologically validated literature on the shedding process. Section D provided existing cleavage site information. The protein sequence structure was depicted as well, in which the extracellular domain regions are marked with blue color and each protease cleavage site is labeled with an asterisk Fig. 4 Web interface for ShedP prediction. To predict the shedding events, the users can insert the protein sequence (FASTA format) of a queried protein in "Prediction" pages. In the prediction result pages, the ShedP prediction results will be revealed. The protein will be regarded as positive and predicted to be shed if the ShedP prediction value is greater than or equal to 0.5, otherwise predicted as negative and nonshed Additional file Additional file 1: Table S1 . The details of the identified 401 shed membrane proteins including the protein UniProt ID and the PubMed ID for literature references. Table S2 

Secretome proteomics for discovery of cancer biomarkers

Cytokines as new treatment targets in chronic heart failure

Protein ectodomain shedding

Ectdomain shedding and regulated intracellular proteolysis in the central nervous system

Molecular and cellular mechanisms of ectodomain shedding

Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism

Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors

PMAP: databases for analyzing proteolytic events and pathways

Human protein reference database and human proteinpedia as discovery tools for systems biology

Proteomic analyses reveal an acidic prime side specificity for the astacin metalloprotease family reflected by physiological substrates

Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites

SecretePipe: a screening pipeline for secreted proteins with competence to identify potential membrane-bound shed markers

UniProt: a hub for protein information

Support vector network

Prediction of protein cellular attributes using pseudo-amino acid composition

Copper modulates zinc metalloproteinase-dependent ectodomain shedding of key signaling and adhesion proteins and promotes the invasion of prostate cancer epithelial cells

sE-cadherin serves as a diagnostic and predictive parameter in prostate cancer patients

Soluble E-cadherin as a diagnostic and prognostic marker in gastric carcinoma

ADAM12-cleaved ephrin-A1 contributes to lung metastasis

Shed Syndecan-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer

Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases

Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med

The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer

Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis

Syndecan-4 shedding is involved in the oxidative stress and inflammatory responses in left atrial tissue with valvular atrial fibrillation

Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression

Increased ectodomain shedding of cell adhesion molecule 1 as a cause of type II alveolar epithelial cell apoptosis in patients with idiopathic interstitial pneumonia

Increased ectodomain shedding of cell adhesion molecule 1 from pancreatic islets in type 2 diabetic pancreata: correlation with hemoglobin A1c levels

Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17

Ectodysplasin is released by proteolytic shedding and binds to the EDAR protein

Soluble CD200 is critical to engraft chronic lymphocytic leukemia cells in immunocompromised mice

An RGD motif present in cadherin 17 induces integrin activation and tumor growth

Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes

Circulating soluble LR11, a novel marker of smooth muscle cell proliferation, is enhanced after coronary stenting in response to vascular injury

Enhanced circulating soluble LR11 in patients with coronary organic stenosis

Enhanced circulating soluble LR11 in patients with diabetic retinopathy

Soluble collectin-12 (CL-12) is a pattern recognition molecule initiating complement activation via the alternative pathway

Stimulation of plateletderived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways

Shedding of soluble platelet-derived growth factor receptor-beta from human brain pericytes

Identification of protein tyrosine phosphatase receptor gamma extracellular domain (sPTPRG) as a natural soluble protein in plasma

Emerging roles for ectodomain shedding in the regulation of inflammatory responses

Human P2X7 receptor activation induces the rapid shedding of CXCL16

CD30 shedding from Karpas 299 lymphoma cells is mediated by TNF-alpha-converting enzyme

Metalloproteases regulate T-cell proliferation and effector function via LAG-3

B cell activation leads to shedding of complement receptor type II (CR2/CD21)

EphA4 receptor shedding regulates spinal motor axon guidance

TACE cleaves neogenin to desensitize cortical neurons to the repulsive guidance molecule

Neural cell adhesion molecule function is regulated by metalloproteinase-mediated ectodomain release

Zinc metalloproteinase-mediated cleavage of the human Nogo-66 receptor

TACEinduced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin

Junctional adhesion molecule-C is a soluble mediator of angiogenesis

Sprouting angiogenesis is regulated by shedding of the C-type lectin family 14, member A (CLEC14A) ectodomain, catalyzed by rhomboid-like 2 protein (RHBDL2)

Specific inhibition of ectodomain shedding of glycoprotein Ibalpha by targeting its juxtamembrane shedding cleavage site

Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands

Tumor necrosis factoralpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability

Evidence for a critical role of the tumor necrosis factor alpha convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR)

Photic injury promotes cleavage of p75NTR by TACE and nuclear trafficking of the p75 intracellular domain

An emerging role of Sonic hedgehog shedding as a modulator of heparan sulfate interactions

Nuclear signalling by tumour-associated antigen EpCAM

Cleavage of transmembrane junction proteins and their role in regulating epithelial homeostasis. Tissue barriers

Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation

Effect of tissue inhibitor of metalloproteinases 3 on DLK1 shedding in cultured human pre-adipocytes and implications for adipose tissue remodelling

Formation of Pmel17 amyloid is regulated by juxtamembrane metalloproteinase cleavage, and the resulting C-terminal fragment is a substrate for gamma-secretase

Tmem27 dimerization, deglycosylation, plasma membrane depletion, and the extracellular Phe-Phe motif are negative regulators of cleavage by Bace2

Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation

Analysis of the C-terminal structure of urinary Tamm-Horsfall protein reveals that the release of the glycosyl phosphatidylinositolanchored counterpart from the kidney occurs by phenylalanine-specific proteolysis

Unaltered cleavage and secretion of angiotensin-converting enzyme in tumor necrosis factor-alpha-converting enzyme-deficient mice

The conversion of the human membrane-associated folate binding protein (folate receptor) to the soluble folate binding protein by a membrane-associated metalloprotease

Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier

Identification of cleavage sites leading to the shed form of the anti-aging protein klotho

Klotho is a substrate for alpha-, beta-and gamma-secretase

Systematic proteomic analysis identifies beta-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic betacells

Deciphering the human platelet sheddome

Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons

Proteolytic cleavage of human acid-sensing ion channel 1 by the serine protease matriptase

Adrenergic agonists mediate enhancement of beta1-adrenergic receptor N-terminal cleavage and stabilization in vivo and in vitro

Studies on the effect of lysosomotropic agents on the release of Gal beta 1-4GlcNAc alpha-2,6-sialytransferase from rat liver slices during the acute-phase response

Abrogation of IFNgamma mediated epithelial barrier disruption by serine protease inhibition

ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function

Shedding of collagen XXIII is mediated by furin and depends on the plasma membrane microenvironment

Type XXIII collagen, a new transmembrane collagen identified in metastatic tumor cells

Characterisation of endothelin converting enzyme-1 shedding from endothelial cells

Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium

IgLON cell adhesion molecules are shed from the cell surface of cortical neurons to promote neuronal growth

The N-terminal ectodomain of Ninjurin1 liberated by MMP9 has chemotactic activity

Shedding of epithin/PRSS14 is induced by TGF-beta and mediated by tumor necrosis factor-alpha converting enzyme

Soluble epithin/PRSS14 secreted from cancer cells contains active angiogenic potential

A disintegrin and metalloproteinase 9 is involved in ectodomain shedding of receptor-binding cancer antigen expressed on SiSo cells

Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form

N-glycosylation is required for matriptase-2 autoactivation and ectodomain shedding

Soluble CD137 (4-1BB) ligand is released following leukocyte activation and is found in sera of patients with hematological malignancies

The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity

Crosstalk of EDA-A2/ XEDAR in the p53 signaling pathway

Agonist-regulated cleavage of the extracellular domain of parathyroid hormone receptor type 1

Transmembrane semaphorin5B is proteolytically processed into a repulsive neural guidance cue

Ligand-induced cleavage of the V2 vasopressin receptor by a plasma membrane metalloproteinase

Membrane targeting, shedding and protein interactions of brain acetylcholinesterase

Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases

Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid

Mannose 6-phosphate/insulin-like growth factor II-binding proteins in human serum and urine. Their relation to the mannose 6-phosphate/ insulin-like growth factor II receptor

Brain ischaemia induces shedding of a BDNF-scavenger ectodomain from TrkB receptors by excitotoxicity activation of metalloproteinases and gamma-secretases

Golgi and secreted galactosyltransferase

Transition of galactosyltransferase 1 from trans-Golgi cisterna to the trans-Golgi network is signal mediated

A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1

Proteolytic shedding of the extracellular domain of photoreceptor cadherin. Implications for outer segment assembly

Free circulating soluble CD52 as a tumor marker in chronic lymphocytic leukemia and its implication in therapy with anti-CD52 antibodies

Biological function of the soluble CEACAM1 protein and implications in TAP2-deficient patients

Shedding of CD9 antigen by bone marrow cells from patients with acute lymphoblastic leukaemia

Shedding of CD9 antigen in acute lymphoblastic leukemia

A soluble form of the MHC class I-specific CD160 receptor is released from human activated NK lymphocytes and inhibits cell-mediated cytotoxicity

CD48: A co-stimulatory receptor of immunity

Detection of a soluble form of the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis

2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes

CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells

Shear stressact as repulsive guidance cues for Unc5-positive neurons

Long-term depression-inducing stimuli promote cleavage of the synaptic adhesion molecule NGL-3 through NMDA receptors, matrix metalloproteinases and presenilin/gamma-secretase

Paracrine regulation of growth factor signaling by shed leucine-rich repeats and immunoglobulin-like domains 1

Soluble LRIG2 ectodomain is released from glioblastoma cells and promotes the proliferation and inhibits the apoptosis of glioblastoma cells in vitro and in vivo in a similar manner to the full-length LRIG2

Human epidermal Langerhans cells secrete a soluble receptor for IgG (Fc gamma RII/CD32) that inhibits the binding of immune complexes to Fc gamma R+ cells

NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17)

ADAM17 cleaves CD16b (FcgammaRIIIb) in human neutrophils

gamma-Secretasemediated release of the low density lipoprotein receptor-related protein 1B intracellular domain suppresses anchorage-independent growth of neuroglioma cells

Neurotrophins regulate ApoER2 proteolysis through activation of the Trk signaling pathway

Regulation of ApoE receptor proteolysis by ligand binding

Ectodomain shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1) is induced by Vascular Endothelial Growth Factor a (VEGF-a)

The glycosylphosphatidylinositol-anchored form and the transmembrane form of CD58 are released from the cell surface upon antibody binding

TNFalpha-converting enzyme cleaves the macrophage colony-stimulating factor receptor in macrophages undergoing activation

Human dendritic cells shed a functional, soluble form of the mannose receptor

A functional soluble form of the murine mannose receptor is produced by macrophages in vitro and is present in mouse serum

Tumor necrosis factor-alpha-converting enzyme controls surface expression of c-Kit and survival of embryonic stem cell-derived mast cells

Identification and characterization of a soluble c-kit receptor produced by human hematopoietic cell lines

Soluble vascular adhesion protein-1 accumulates in proliferative diabetic retinopathy

Release of MICB molecules by tumor cells: mechanism and soluble MICB in sera of cancer patients

Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia

Circulating CD33 and its clinical value in acute leukemia

Analysis of the CD33-related siglec family reveals that Siglec-9 is an endocytic receptor expressed on subsets of acute myeloid leukemia cells and absent from normal hematopoietic progenitors

Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells

The function of neurofascin155 in oligodendrocytes is regulated by metalloprotease-mediated cleavage and ectodomain shedding

Activity-dependent proteolytic cleavage of neuroligin-1

The shed ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell transformation

VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling

Proteolytic release of soluble UL16-binding protein 2 from tumor cells

The noncatalytic TrkCNC2 receptor is cleaved by metalloproteases upon neurotrophin-3 stimulation

Posttranslational proteolytic processing of Leda-1/Pianp involves cleavage by MMPs, ADAM10/17 and gamma-secretase

Counter-regulation of the ligand-receptor pair Leda-1/ Pianp and Pilralpha during the LPS-mediated immune response of murine macrophages

Shedding of the 67-kD laminin receptor by human cancer cells

Functional regulation of semaphorin receptors by proprotein convertases

A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

Processing of the human protocadherin Fat1 and translocation of its cytoplasmic domain to the nucleus

A soluble form of the giant cadherin Fat1 is released from pancreatic cancer cells by ADAM10 mediated ectodomain shedding

The "a disintegrin and metalloprotease" (ADAM) family of sheddases: physiological and cellular functions

Protocadherin-12 cleavage is a regulated process mediated by ADAM10 protein: evidence of shedding up-regulation in pre-eclampsia

Regulated ADAM10-dependent ectodomain shedding of gammaprotocadherin C3 modulates cell-cell adhesion

Metalloproteinase-and gamma-secretase-mediated cleavage of protein-tyrosine phosphatase receptor type Z

EGFR signaling leads to downregulation of PTP-LAR via TACE-mediated proteolytic processing

Proteolytic processing of the receptor-type protein tyrosine phosphatase PTPBR7

Cellular redistribution of protein tyrosine phosphatases LAR and PTPsigma by inducible proteolytic processing

Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma

Identification of ROBO1 as a novel hepatocellular carcinoma antigen and a potential therapeutic and diagnostic target

Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

The SLAM family member CD84 is regulated by ADAM10 and calpain in platelets

Neuronal brain-derived neurotrophic factor is synthesized in excess, with levels regulated by sortilin-mediated trafficking and lysosomal degradation

Nucleotide-induced membrane-proximal proteolysis controls the substrate specificity of T cell ecto-ADPribosyltransferase ARTC2.2

T-cell immunoglobulin and mucin domain 2 (TIM-2) is a target of ADAM10-mediated ectodomain shedding

Cleavage of lymphocyte surface antigens CD2, CD4, and CD8 by polymorphonuclear leukocyte elastase and cathepsin G in patients with cystic fibrosis

Identification of a natural soluble form of human CD5

Immunochemical analysis of the released Leu-2 (T8) molecule

Spontaneous release of the Leu-2 (T8) molecule from human T cells

Detection of circulating soluble CD28 in patients with systemic lupus erythematosus, primary Sjogren's syndrome and systemic sclerosis

TACE-mediated ectodomain shedding of the type I TGF-beta receptor downregulates TGF-beta signaling

Cleavage of the human thyrotropin receptor by ADAM10 is regulated by thyrotropin

Soluble CD86 is a costimulatory molecule for human T lymphocytes

Metalloproteinasedependent TLR2 ectodomain shedding is involved in soluble toll-like receptor 2 (sTLR2) production

Roles of the cleaved N-terminal TLR3 fragment and cell surface TLR3 in double-stranded RNA sensing

Toll-like receptor (TLR4) shedding and depletion: acute proximal tubular cell responses to hypoxic and toxic injury

The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor

Negative regulation of signaling by a soluble form of toll-like receptor 9

Release of soluble transferrin receptor from the surface of human leukemic HL60 cells

Ectodomain shedding of TbetaRIII is required for TbetaRIII-mediated suppression of TGF-beta signaling and breast cancer migration and invasion

The structure of the extracellular domain of triggering receptor expressed on myeloid cells like transcript-1 and evidence for a naturally occurring soluble fragment

Metalloproteinases shed TREM-1 ectodomain from lipopolysaccharide-stimulated human monocytes

Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gammasecretase-dependent intramembranous cleavage

Receptor activator of NF-kappaB (RANK) ligand induces ectodomain shedding of RANK in murine RAW264.7 macrophages

Membrane protease proteomics: Isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates

Proteolysis-induced N-terminal ectodomain shedding of the integral membrane glycoprotein CUB domaincontaining protein 1 (CDCP1) is accompanied by tyrosine phosphorylation of its C-terminal domain and recruitment of Src and PKCdelta

Cardiomyocytes induce macrophage receptor shedding to suppress phagocytosis

The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage

Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum

Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis

Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells

A disintegrin and metalloprotease 10 is a novel mediator of vascular endothelial growth factor-induced endothelial cell function in angiogenesis and is associated with atherosclerosis

ADAM17 (TACE) regulates TGFbeta signaling through the cleavage of vasorin

Nardilysin-dependent proteolysis of cellassociated VTCN1 (B7-H4) marks type 1 diabetes development

LIV-1 ZIP ectodomain shedding in prioninfected mice resembles cellular response to transition metal starvation

Novel proteolytic processing of the ectodomain of the zinc transporter ZIP4 (SLC39A4) during zinc deficiency is inhibited by acrodermatitis enteropathica mutations

Maturation of secreted meprin alpha during biosynthesis: role of the furin site and identification of the COOH-terminal amino acids of the mouse kidney metalloprotease subunit

Increased levels of soluble CD226 in sera accompanied by decreased membrane CD226 expression on peripheral blood mononuclear cells from cancer patients

Soluble CD276 (B7-H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum

Local secretion/shedding of tumor-derived CD83 molecules as a novel tumor escape mechanism

Ectodomain shedding of neuroglycan C, a brain-specific chondroitin sulfate proteoglycan, by TIMP-2-and TIMP-3-sensitive proteolysis

ten Dijke P. Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis

MMP-14 is expressed in preeclamptic placentas and mediates release of soluble endoglin

The FGFRL1 receptor is shed from cell membranes, binds fibroblast growth factors (FGFs), and antagonizes FGF signaling in Xenopus embryos

Presenilin/gamma-secretase and alphasecretase-like peptidases cleave human MHC Class I proteins

Insights into ectodomain shedding and processing of protein-tyrosine pseudokinase 7 (PTK7)

The insulin-like growth factor 1 (IGF-1) receptor is a substrate for gamma-secretase-mediated intramembrane proteolysis

Pericellular proteolysis in cancer

Interferon-gamma enhances expression of secretory component, the epithelial receptor for polymeric immunoglobulins

Reducing agents induce thrombomodulin shedding in human endothelial cells

Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2

Synapse maturation by activity-dependent ectodomain shedding of SIRPalpha

Cytokine stimulated vascular cell adhesion molecule-1 (VCAM-1) ectodomain release is regulated by TIMP-3

VIP36 protein is a target of ectodomain shedding and regulates phagocytosis in macrophage Raw 264.7 cells

Differential regulation and function of CD73, a glycosyl-phosphatidylinositol-linked 70-kD adhesion molecule, on lymphocytes and endothelial cells

The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3

Proteolytic cleavage of the EMR2 receptor requires both the extracellular stalk and the GPS motif

Epithelial sodium channels are activated by furin-dependent proteolysis

Proteolytic processing of the epithelial sodium channel gamma subunit has a dominant role in channel activation

ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors

Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival

Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-alpha: impact on gastrointestinal cancers driven by secondary bile acids

Human amyloid precursor-like protein 1-cDNA cloning, ectopic expression in COS-7 cells and identification of soluble forms in the cerebrospinal fluid

Processing of betaamyloid precursor-like protein-1 and −2 by gamma-secretase regulates transcription

Shedding of the amyloid precursor protein-like protein APLP2 by disintegrinmetalloproteinases

Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndromecoronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)

Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry

Proteolytic cleavage of annexin 1 by human leukocyte elastase

Matrilysin (matrix metalloprotease-7) cleaves membrane-bound annexin II and enhances binding of tissue-type plasminogen activator to cancer cell surfaces

Ectodomain shedding and autocleavage of the cardiac membrane protease corin

Soluble Lutheran/basal cell adhesion molecule is detectable in plasma of hepatocellular carcinoma patients and modulates cellular interaction with laminin-511 in vitro

Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN

Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells

Endoproteolytic cleavage in the extracellular domain of the integral plasma membrane protein CE9 precedes its redistribution from the posterior to the anterior tail of the rat spermatozoon during epididymal maturation

Characterization of the ectodomain shedding of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)

Prodomain processing of Asp1 (BACE2) is autocatalytic

ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling

Soluble N-cadherin in human biological fluids

Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

Impaired autoproteolytic cleavage of mCLCA6, a murine integral membrane protein expressed in enterocytes, leads to cleavage at the plasma membrane instead of the endoplasmic reticulum

Alcadein cleavages by amyloid beta-precursor protein (APP) alpha-and gamma-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease-related gamma-secretase dysfunction

Calsyntenin-1, a proteolytically processed postsynaptic membrane protein with a cytoplasmic calcium-binding domain

Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109

The ALCAM shedding by the metalloprotease ADAM17/TACE is involved in motility of ovarian carcinoma cells

The CD27 membrane receptor, a lymphocyte-specific member of the nerve growth factor receptor family, gives rise to a soluble form by protein processing that does not involve receptor endocytosis

Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca(2+) influx and PKC activation

Shedding and enrichment of the glycolipid-anchored complement lysis inhibitor protectin (CD59) into milk fat globules

Tumor suppressor cell adhesion molecule 1 (CADM1) is cleaved by a disintegrin and metalloprotease 10 (ADAM10) and subsequently cleaved by gamma-secretase complex

Two separate metalloproteinase activities are responsible for the shedding and processing of the NG2 proteoglycan in vitro

The shed ectodomain of type XIII collagen affects cell behaviour in a matrix-dependent manner

Extracellular phosphorylation of collagen XVII by ecto-casein kinase 2 inhibits ectodomain shedding

CLAC: a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC-P/collagen type XXV

The hemopexin-like C-terminal domain of membrane type 1 matrix metalloproteinase regulates proteolysis of a multifunctional protein, gC1qR

Effects of O-linked glycosylation on the cell surface expression and stability of decay-accelerating factor, a glycophospholipid-anchored membrane protein

The Coxsackievirus and Adenovirus Receptor (CAR) undergoes ectodomain shedding and regulated intramembrane proteolysis (RIP)

MMP-7) cleaves C-type lectin domain family 3 member A (CLEC3A) on tumor cell surface and modulates its cell adhesion activity

CRIM1 regulates the rate of processing and delivery of bone morphogenetic proteins to the cell surface

Crimpy enables discrimination of presynaptic and postsynaptic pools of a BMP at the Drosophila neuromuscular junction

A soluble form of the murine common gamma chain is present at high concentrations in vivo and suppresses cytokine signaling

Cellular roles of ADAM12 in health and disease

The fate of desmosomal proteins in apoptotic cells

Nitric oxide inhibits the shedding of the glycosylphosphatidylinositol-anchored dipeptidase from porcine renal proximal tubules

The ADAM15 ectodomain is shed from secretory exosomes

Autolytic processing at Glu586-Ser587 within the cysteine-rich domain of human adamalysin 19/disintegrin-metalloproteinase 19 is necessary for its proteolytic activity

ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein

A systematic study of modulation of ADAM-mediated ectodomain shedding by site-specific O-glycosylation

Ectodomain shedding of CD200 from the B-CLL cell surface is regulated by ADAM28 expression

The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion

Enzymatic processing of betadystroglycan recombinant ectodomain by MMP-9: identification of the main cleavage site

Characterization of the protease activity that cleaves the extracellular domain of beta-dystroglycan

Rosmarinic acid down-regulates endothelial protein C receptor shedding in vitro and in vivo

The extracellular N terminus of the endothelin B (ETB) receptor is cleaved by a metalloprotease in an agonistdependent process

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma

A residue in the S2 subsite controls substrate selectivity of matrix metalloproteinase-2 and matrix metalloproteinase-9

Ephrin-B2-induced cleavage of EphB2 receptor is mediated by matrix metalloproteinases to trigger cell repulsion

The C-terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells

Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM

Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab

Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: involvement of Src tyrosine kinase

TNF-alpha and IL-1 upregulate membrane-bound and soluble E-selectin through a common pathway

Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1

Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1)

Ectodomain shedding of furin: kinetics and role of the cysteine-rich region

Shed' furin: mapping of the cleavage determinants and identification of its C-terminus

Secreted gliomedin is a perinodal matrix component of peripheral nerves

Activity-dependent cleavage of brain glutamic acid decarboxylase 65 by calpain

TCR activation eliminates glutamate receptor GluR3 from the cell surface of normal human T cells, via an autocrine/paracrine granzyme B-mediated proteolytic cleavage

Activity-dependent shedding of the NMDA receptor glycine binding site by matrix metalloproteinase 3: a PUTATIVE mechanism of postsynaptic plasticity

Effect of glypican-1 covalently attached chains on turkey myogenic satellite cell proliferation, differentiation, and fibroblast growth factor 2 responsiveness

Glypican-3 as a serum marker for hepatocellular carcinoma

Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements

DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites

Expression and immunoaffinity purification of recombinant soluble human GPR56 protein for the analysis of GPR56 receptor shedding by ELISA

Growth hormone (GH)-induced dimerization inhibits phorbol esterstimulated GH receptor proteolysis

Purification and characterization of hepatocyte growth factor (HGF)-converting enzyme: activation of pro-HGF

Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling

ADAM10/17-dependent release of soluble c-Met correlates with hepatocellular damage

CD74 is a member of the regulated intramembrane proteolysis-processed protein family

Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes

Functional and structural analysis of VLA-4 integrin alpha 4 subunit cleavage

Integrin alpha6 cleavage: a novel modification to modulate cell migration

An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase

Heat shockinduced shedding of cell surface integrins in A549 human lung tumor cells in culture

Matrix metalloproteinase-2 cleavage of the beta1 integrin ectodomain facilitates colon cancer cell motility

MMP9 cleavage of the beta4 integrin ectodomain leads to recurrent epithelial erosions in mice

Tumor necrosis factor-alpha-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1)

Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor

Natural, proteolytic release of a soluble form of human IL-15 receptor alpha-chain that behaves as a specific, high affinity IL-15 antagonist

M-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages

Different ADAMs have distinct influences on Kit ligand processing: phorbolester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19

Multiple sites of proteolytic cleavage to release soluble forms of hepatocyte growth factor activator inhibitor type 1 from a transmembrane form

ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase

Establishment of an ELISA system for determining soluble LAIR-1 levels in sera of patients with HFRS and kidney transplant

Metalloprotease and serine protease are involved in cleavage of CD43, CD44, and CD16 from stimulated human granulocytes. Induction of cleavage of L-selectin via CD16

CD43, the major sialoglycoprotein of human leukocytes, is proteolytically cleaved from the surface of stimulated lymphocytes and granulocytes

Comparative analysis of gingival crevicular fluid a disintegrin and metalloproteinase 8 levels in health and periodontal disease: A clinicbiochemical study

Use of a mutant cell line to study the kinetics and function of O-linked glycosylation of low density lipoprotein receptors

Linking receptor-mediated endocytosis and cell signaling: evidence for regulated intramembrane proteolysis of megalin in proximal tubule

Regulated proteolytic processing of LRP6 results in release of its intracellular domain

An essential role for ectodomain shedding in mammalian development

Metastasisassociated C4.4A, a GPI-anchored protein cleaved by ADAM10 and ADAM17

Cell surface colonystimulating factor 1 can be cleaved by TNF-alpha converting enzyme or endocytosed in a clathrin-dependent manner

The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein

Processing, shedding, and endocytosis of membrane type 1-matrix metalloproteinase (MT1-MMP)

Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma

Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma

The secreted form of a melanocyte membrane-bound glycoprotein (Pmel17/gp100) is released by ectodomain shedding

ADAM10-mediated release of complement membrane cofactor protein during apoptosis of epithelial cells

Complement inhibitor membrane cofactor protein (MCP; CD46) is constitutively shed from cancer cell membranes in vesicles and converted by a metalloproteinase to a functionally active soluble form

Meprin alpha and meprin beta: Procollagen proteinases in health and disease

Phorbol 12-myristate 13-acetate-induced ectodomain shedding and phosphorylation of the human meprinbeta metalloprotease

Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer

NKG2D and DNAM-1 Ligands: Molecular Targets for NK Cell-Mediated Immunotherapeutic Intervention in Multiple Myeloma

Tumor-associated MICA is shed by ADAM proteases

Shedding as a mechanism of down-modulation of CD14 on stimulated human monocytes

Tumor necrosis factor-alpha converting enzyme/ADAM 17 mediates MUC1 shedding

MT1-MMP mediates MUC1 shedding independent of TACE/ADAM17

A novel metalloproteinase associated with brain myelin membranes. Isolation and characterization

Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Ectodomain shedding of nectin-1 regulates the maintenance of dendritic spine density

Activitydependent alpha-cleavage of nectin-1 is mediated by a disintegrin and metalloprotease 10 (ADAM10)

Metalloproteasemediated tumor cell shedding of B7-H6, the ligand of the natural killer cellactivating receptor NKp30

Lrig2 Negatively Regulates Ectodomain Shedding of Axon Guidance Receptors by ADAM Proteases

Production of soluble Neprilysin by endothelial cells

Function of an axonal chemoattractant modulated by metalloprotease activity

Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins

Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death

A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE

Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2

Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins

mGluR1/5-dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE

Estrogen decrease in tight junctional resistance involves matrix-metalloproteinase-7-mediated remodeling of occludin

Estrogen abrogates transcervical tight junctional resistance by acceleration of occludin modulation

Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome: a novel marker for early diagnosis

Shedding of PECAM-1 during HIV infection: a potential role for soluble PECAM-1 in the pathogenesis of NeuroAIDS

Shear-induced interaction of platelets with von Willebrand factor results in glycoprotein Ibalpha shedding

Platelet receptor expression and shedding: glycoprotein Ib-IX-V and glycoprotein VI

Controlled shedding of platelet glycoprotein (GP)VI and GPIb-IX-V by ADAM family metalloproteinases

GI24 enhances tumor invasiveness by regulating cell surface membrane-type 1 matrix metalloproteinase

Characterization of cisautoproteolysis of polycystin-1, the product of human polycystic kidney disease 1 gene

Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing

Wound-induced HB-EGF ectodomain shedding and EGFR activation in corneal epithelial cells

Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy

CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling

LRP1 shedding in human brain: roles of ADAM10 and ADAM17

Metalloproteinase-dependent cleavage of neuregulin and autocrine stimulation of vascular endothelial cells

DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death

Regulated shedding of PAR1 N-terminal exodomain from endothelial cells

Proteinase-activated receptor-2 and human lung epithelial cells: disarming by neutrophil serine proteinases

Defective cleavage of membrane bound TGFalpha leads to enhanced activation of the EGF receptor in malignant cells

Helicobacter pylori-induced gastric mucosal TGFalpha ectodomain shedding and EGFR transactivation involves Rac1/p38

MAPK-dependent TACE activation

Multiple metalloproteinases process protransforming growth factor-alpha (proTGF-alpha)

The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1

Sehara-Fujisawa A. Roles of ADAM8 in elimination of injured muscle fibers prior to skeletal muscle regeneration

Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells

HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer

Identification of target proteins of N-acetylglucosaminyl transferase V in human colon cancer and implications of protein tyrosine phosphatase kappa in enhanced cancer cell migration

Increased proteolytic processing of protein tyrosine phosphatase mu in confluent vascular endothelial cells: the role of PC5, a member of the subtilisin family

Proteolytic cleavage of protein tyrosine phosphatase mu regulates glioblastoma cell migration

RECK forms cowbell-shaped dimers and inhibits matrix metalloproteinase-catalyzed cleavage of fibronectin

Tumor necrosis factor alpha-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163

Calpain-mediated proteolytic cleavage of the neuronal glycine transporter, GlyT2

beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor proteincleaving enzyme (BACE1) and gamma-secretase

Voltage-gated Na + channels: potential for beta subunits as therapeutic targets

Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members

Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activation

Regulation of the activity of matriptase on epithelial cell surfaces by a blood-derived factor

Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration

Matrix metalloproteinasedependent shedding of syndecan-3, a transmembrane heparan sulfate proteoglycan, in Schwann cells

Syndecan 3 intramembrane proteolysis is presenilin/gammasecretase-dependent and modulates cytosolic signaling

Increased soluble CD4 in serum of rheumatoid arthritis patients is generated by matrix metalloproteinase (MMP)-like proteinases

Release of thy-1.2 and thy-1.1 from lymphoblastoid cells: partial characterization and antigenicity of shed material

Characterization of a hydrophilic form of Thy-1 purified from human cerebrospinal fluid

Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis

Matrix metalloproteinases cleave tissue factor pathway inhibitor. Effects on coagulation

Phorbol ester-induced shedding of the prostate cancer marker transmembrane protein with epidermal growth factor and two follistatin motifs 2 is mediated by the disintegrin and metalloproteinase-17

ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties

Glycoprotein nonmetastatic melanoma protein b, a melanocytic cell marker, is a melanosome-specific and proteolytically released protein

Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia

Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival

Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand

RNF41 (Nrdp1) controls type 1 cytokine receptor degradation and ectodomain shedding

Two functionally distinct isoforms of TL1A (TNFSF15) generated by differential ectodomain shedding

Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity

Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23

In rheumatoid arthritis soluble CD30 ligand is present at high levels and induces apoptosis of CD30(+)T cells

Membrane-anchored CD40 is processed by the tumor necrosis factor-alphaconverting enzyme. Implications for CD40 signaling

Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices

Secretion of VEGF-165 has unique characteristics, including shedding from the plasma membrane

Characterization of a novel rat brain glycosylphosphatidylinositol-anchored protein (Kilon), a member of the IgLON cell adhesion molecule family

Signal peptide prediction based on analysis of experimentally verified cleavage sites

Caspase-specific and nonspecific in vivo protein processing during Fas-induced apoptosis

Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells

Determination of the molecular structure of the human free secretory component

Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation

Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity

Neuroglycan C, a novel membrane-spanning chondroitin sulfate proteoglycan that is restricted to the brain

The limbic system-associated membrane protein is an Ig superfamily member that mediates selective neuronal growth and axon targeting

Comparison of amino acid sequences of two human histocompatibility antigens, HLA-A2 and HLA-B7: location of putative alloantigenic sites

The murine P84 neural adhesion molecule is SHPS-1, a member of the phosphatase-binding protein family

Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides

Predictions of Cleavability of Calpain Proteolysis by Quantitative Structure-Activity Relationship Analysis Using Newly Determined Cleavage Sites and Catalytic Efficiencies of an Oligopeptide Array

Identification of shed proteins from Chinese hamster ovary cells: application of statistical confidence using human and mouse protein databases

Proteomic analysis of ovarian cancer cells reveals dynamic processes of protein secretion and shedding of extra-cellular domains

Rapid temporal dynamics of transcription, protein synthesis, and secretion during macrophage activation

HCSD: the human cancer secretome database

Sys-BodyFluid: a systematical database for human body fluid proteome research

SPD-a web-based secreted protein database

LOCATE: a mammalian protein subcellular localization database

We thank Dr. Hsuan-Cheng Huang at the Institute of Biomedical Informatics, National Yang Ming University, for support and inspiring discussions.

This article has been published as part of BMC Bioinformatics Volume 18 Supplement 3, 2017. Selected articles from the 15th Asia Pacific Bioinformatics Conference (APBC 2017): bioinformatics. The full contents of the supplement are available online https://

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