BioPAX pathway converted from "Formation of the cornified envelope" in the Reactome database. Formation of the cornified envelope As keratinocytes progress towards the upper epidermis, they undergo a unique process of cell death termed cornification (Eckhart et al. 2013). This involves the crosslinking of keratinocyte proteins such as loricrin and involucrin by transglutaminases and the breakdown of the nucleus and other organelles by intracellular and secreted proteases (Eckhart et al. 2000, Denecker et al. 2008). This process is strictly regulated by the Ca2+ concentration gradient in the epidermis (Esholtz et al. 2014). Loricrin and involucrin are encoded in ‘Epidermal Differentiation Complex’ linked to a large number of genes encoding nonredundant components of the CE (Kypriotou et al. 2012, Niehues et al. 2016). Keratinocytes produce specialized proteins and lipids which are used to construct the cornified envelope (CE), a heavily crosslinked submembranous layer that confers rigidity to the upper epidermis, allows keratin filaments to attach to any location in the cell membrane (Kirfel et al. 2003) and acts as a water-impermeable barrier. The CE has two functional parts: covalently cross-linked proteins (10 nm thick) that comprise the backbone of the envelope and covalently linked lipids (5 nm thick) that coat the exterior (Eckert et al. 2005). Desmosomal components are crosslinked to the CE to form corneodesmosomes, which bind cornified cells together (Ishida-Yamamoto et al. 2011). Mature terminally differentiated cornified cells consist mostly of keratin filaments covalently attached to the CE embedded in lipid lamellae (Kalinin et al. 2002). The exact composition of the cornified envelope varies between epithelia (Steinert et al. 1998); the relative amino-acid composition of the proteins used may determine differential mechanical properties (Kartasova et al. 1996). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 LEFT-TO-RIGHT Envoplakin binds periplakin Envoplakin (EVPL) is insoluble under physiological conditions but soluble as a heterodimer with periplakin (PPL) (Kalinin et al. 2004). The heterodimers provide a firm but flexible structures (Al-Jassar et al. 2013). EVPL and PPL deposition and crosslinking are amongst the earliest events of cornification (Kalinin et al. 2002, Candi et al. 2005). They partially colocalize with desmosomal proteins and keratin intermediate filaments (Ruhrberg et al. 1996, DiColandrea et al. 2000), linking the cornified envelope to desmosomes and keratin filaments (Ruhrberg et al. 1996, 1997). PPL also associates with cortical actin at the interdesmosomal plasma membrane (DiColandrea et al. 2000, Groot et al. 2004). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 EVPL Envoplakin EVPL_HUMAN Reactome DB_ID: 6810853 cytosol GENE ONTOLOGY GO:0005829 UniProt:Q92817 EVPL EVPL FUNCTION Component of the cornified envelope of keratinocytes. May link the cornified envelope to desmosomes and intermediate filaments.SUBUNIT May form a homodimer or a heterodimer with PPL.TISSUE SPECIFICITY Exclusively expressed in stratified squamous epithelia.INDUCTION During differentiation of epidermal keratinocytes.SIMILARITY Belongs to the plakin or cytolinker family. Homo sapiens NCBI Taxonomy 9606 UniProt Q92817 1 EQUAL 2033 EQUAL Reactome Database ID Release 78 6810853 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810853 Reactome R-HSA-6810853 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810853.1 Reactome http://www.reactome.org PPL Periplakin PEPL_HUMAN Reactome DB_ID: 6810850 UniProt:O60437 PPL PPL KIAA0568 FUNCTION Component of the cornified envelope of keratinocytes. May link the cornified envelope to desmosomes and intermediate filaments. May act as a localization signal in PKB/AKT-mediated signaling.SUBUNIT Homodimer or a heterodimer with EVPL (PubMed:9412476). Found in a complex composed of PPL (via C-terminal linker domain), BFSP1 and BFSP2 in the retinal lens (By similarity). Within the complex interacts (via C-terminal linker domain) with BFSP2 (By similarity). Interacts with VIM (By similarity). Binds to the PH domain of AKT1 (PubMed:12244133). Interacts with FCGR1A (PubMed:15229321). May interact with PPHLN1 (PubMed:12853457).TISSUE SPECIFICITY Expressed in stratified squamous epithelia and in some other epithelia.DEVELOPMENTAL STAGE Expressed in the epidermis, nuclei of dermal fibroblasts, cell periphery of flattened keratinocytes, and dermal and epithelial cells lining the excretory ducts of the sweat glands in neonatal foreskin.INDUCTION During differentiation of epidermal keratinocytes.SIMILARITY Belongs to the plakin or cytolinker family. UniProt O60437 1 EQUAL 1756 EQUAL Reactome Database ID Release 78 6810850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810850 Reactome R-HSA-6810850 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810850.1 EVPL:PPL Reactome DB_ID: 6814178 1 1 Reactome Database ID Release 78 6814178 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814178 Reactome R-HSA-6814178 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814178.1 Reactome Database ID Release 78 6810843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810843 Reactome R-HSA-6810843 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810843.1 15033990 Pubmed 2004 Co-assembly of envoplakin and periplakin into oligomers and Ca(2+)-dependent vesicle binding: implications for cornified cell envelope formation in stratified squamous epithelia Kalinin, Andrey E Idler, William W Marekov, Lyuben N McPhie, P Bowers, Blair Steinert, Peter M Steven, Alasdair C J. Biol. Chem. 279:22773-80 8707850 Pubmed 1996 Envoplakin, a novel precursor of the cornified envelope that has homology to desmoplakin Ruhrberg, C Hajibagheri, M A Simon, M Dooley, T P Watt, F M J. Cell Biol. 134:715-29 12210515 Pubmed 2002 Epithelial barrier function: assembly and structural features of the cornified cell envelope Kalinin, Andrey E Kajava, Andrey V Steinert, Peter M Bioessays 24:789-800 11062259 Pubmed 2000 Subcellular distribution of envoplakin and periplakin: insights into their role as precursors of the epidermal cornified envelope DiColandrea, T Karashima, T Määttä, A Watt, F M J. Cell Biol. 151:573-86 9412476 Pubmed 1997 Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin Ruhrberg, C Hajibagheri, M A Parry, D A Watt, F M J. Cell Biol. 139:1835-49 15803139 Pubmed 2005 The cornified envelope: a model of cell death in the skin Candi, Eleonora Schmidt, Rainer Melino, Gerry Nat. Rev. Mol. Cell Biol. 6:328-40 15337775 Pubmed 2004 Kazrin, a novel periplakin-interacting protein associated with desmosomes and the keratinocyte plasma membrane Groot, Karen R Sevilla, Lisa M Nishi, Kazunori DiColandrea, Teresa Watt, Fiona M J. Cell Biol. 166:653-9 23922795 Pubmed 2013 Hinged plakin domains provide specialized degrees of articulation in envoplakin, periplakin and desmoplakin Al-Jassar, Caezar Bernadό, Pau Chidgey, Martyn Overduin, Michael PLoS ONE 8:e69767 LEFT-TO-RIGHT EVL:PPL heterodimer binds the inner surface of the plasma membrane Envoplakin:periplakin heterodimers (EVPL:PPL) bind the plasma membrane. In vitro, EVPL:PPL can bind lipid vesicles in response to increasing Ca2+, suggesting that translocation and binding to the plasma membrane is regulated by elevation of intracellular Ca2+ (Kalinin et al. 2004). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 Cell surface Reactome DB_ID: 983438 plasma membrane GENE ONTOLOGY GO:0005886 Reactome Database ID Release 78 983438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=983438 Reactome R-ALL-983438 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-983438.2 ChEBI 23367 additional information MI MI:0361 EVPL:PPL:Cell surface Reactome DB_ID: 6814188 1 1 Reactome Database ID Release 78 6814188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814188 Reactome R-HSA-6814188 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814188.1 Reactome Database ID Release 78 6814187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814187 Reactome R-HSA-6814187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814187.1 LEFT-TO-RIGHT TGM1 and involucrin bind the plasma membrane Transglutaminase-1 (TGM1) and involucrin (IVL) are expressed shortly after envoplakin and periplakin. TGM1 associates with the plasma membrane via C14-16 fatty-acid adducts on its C-terminus (Steinert et al. 1996). IVL deposition precedes that of most other cornified envelope proteins (Nemes & Steinert 1999). It can bind the plasma membrane in a calcium and phosphatidyl-serine dependent manner, where it becomes a substrate for membrane-bound TGM1 and TGM5 (Nemes et al. 1999, Candi et al. 2001). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 TGM1 Protein-glutamine gamma-glutamyltransferase K ecNumber2.3.2.13/ecNumber TGM1_HUMAN Reactome DB_ID: 6813756 UniProt:P22735 TGM1 TGM1 KTG FUNCTION Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Responsible for cross-linking epidermal proteins during formation of the stratum corneum. Involved in cell proliferation (PubMed:26220141).SUBUNIT Interacts with PLAAT4.PTM Palmitoylated.PTM The membrane anchorage region possesses a cluster of five cysteines within which fatty acid(s) may become thioester-linked. It is subject to phorbol ester-stimulated phosphorylation and is hypersensitive to proteolysis, which releases the enzyme in a soluble form.PTM Tyrosine-phosphorylated.SIMILARITY Belongs to the transglutaminase superfamily. Transglutaminase family. UniProt P22735 1 EQUAL 817 EQUAL Reactome Database ID Release 78 6813756 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6813756 Reactome R-HSA-6813756 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6813756.1 IVL Involucrin INVO_HUMAN Reactome DB_ID: 6810837 UniProt:P07476 IVL IVL FUNCTION Part of the insoluble cornified cell envelope (CE) of stratified squamous epithelia.SUBUNIT Directly or indirectly cross-linked to cornifelin (CNFN).TISSUE SPECIFICITY Keratinocytes of epidermis and other stratified squamous epithelia.PTM Substrate of transglutaminase. Some glutamines and lysines are cross-linked to other involucrin molecules, to other proteins such as keratin, desmoplakin, periplakin and envoplakin, and to lipids like omega-hydroxyceramide.SIMILARITY Belongs to the involucrin family. UniProt P07476 1 EQUAL 585 EQUAL Reactome Database ID Release 78 6810837 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810837 Reactome R-HSA-6810837 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810837.1 IVL:TGM1:Cell surface Reactome DB_ID: 6814746 1 1 1 Reactome Database ID Release 78 6814746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814746 Reactome R-HSA-6814746 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814746.1 Reactome Database ID Release 78 6810899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810899 Reactome R-HSA-6810899 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810899.1 8824274 Pubmed 1996 The transglutaminase 1 enzyme is variably acylated by myristate and palmitate during differentiation in epidermal keratinocytes Steinert, P M Kim, SY Chung, S I Marekov, L N J. Biol. Chem. 271:26242-50 10196183 Pubmed 1999 Involucrin cross-linking by transglutaminase 1. Binding to membranes directs residue specificity Nemes, Z Marekov, L N Steinert, P M J. Biol. Chem. 274:11013-21 10231017 Pubmed 1999 Bricks and mortar of the epidermal barrier Nemes, Z Steinert, P M Exp. Mol. Med. 31:5-19 11443109 Pubmed 2001 Transglutaminase 5 cross-links loricrin, involucrin, and small proline-rich proteins in vitro Candi, E Oddi, S Terrinoni, A Paradisi, A Ranalli, M Finazzi-Agró, A Melino, G J. Biol. Chem. 276:35014-23 LEFT-TO-RIGHT 2.3.2.13 Envoplakin, periplakin, involucrin, SPR binding mediated by TGM1 crosslinking The current model of cornified envelope (CE) formation suggests that crosslinking between envoplakin (EVPL), periplakin (PPL), involucrin (IVL) and small proline-rich proteins (SPRs) results in the formation of a layer along the entire inner surface of the plasma membrane, including desmosomes, forming a scaffold to which other precursors are added to form the mature CE (Steinert & Marekov 1999, Kalinin et al. 2002, Candi et al. 2001). <br><br>Transglutaminases (TGs) are believed to mediate the intramolecular bonds involved in CE formation. They catalyze inter-protein bond formation by forming a thiolester acyl-enzyme intermediate and subsequently transferring the acyl residue to a primary amine (Folk & Finlayson 1977, Folk 1980). The amine acceptor is generally provided by the epsilon-amino group of a protein-bound lysine and the link formed is an N6-(gamma-glutamyl)lysine isopeptide bond.<br><br>CE assembly is thought to be initiated on the inner face of the plasma membrane between desmosomes by the cross-linking of involucrin to itself, to envoplakin and perhaps to periplakin (Steinert & Marekov 1999). The extent of homo- and heterologous cross-linking varies as the CE matures. In the immature CE, EVPL, IVL, SPR1, and SPR2 are largely cross-linked to themselves; EVPL-IVL and IVL-SPR crosslinks are common while cross-links between desmoplakin (DSP) and IVL or DSP and EVPL are not. Later there are many more cross-links between DSP and IVL, DSP and EVL, or IVL and type II keratins. Loricrin (LOR) cross-linking to other protein partners appears later.<br><br>Transglutaminase-1 (TGM1) can crosslink IVL (Simon & Green 1988, Nemes et al. 1999), LOR (Candi et al. 2001), SPR3 (Steinert et al. 1999) and is thought to be responsible for EVPL crosslinking to itself and to IVL (Steinert & Marekov 1999). TGM5 can catalyse homo-crosslinking in LOR, SPR1, SPR2, and IVL, and hetero-crosslinks between LOR-SPR3 (Candi et al. 2001). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 EVPL:PPL:IVL:TGM1:Cell surface Reactome DB_ID: 6814177 1 1 Reactome Database ID Release 78 6814177 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814177 Reactome R-HSA-6814177 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814177.1 ACTIVATION Converted from EntitySet in Reactome TGM1:Ca2+, TGM5:Ca2+ Reactome DB_ID: 6814175 TGM1:Ca2+ Reactome DB_ID: 6814181 TGM1 Protein-glutamine gamma-glutamyltransferase K ecNumber2.3.2.13/ecNumber TGM1_HUMAN Reactome DB_ID: 6813757 1 EQUAL 817 EQUAL Reactome Database ID Release 78 6813757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6813757 Reactome R-HSA-6813757 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6813757.1 1 Ca2+ Calcium calcium(2+) Reactome DB_ID: 74016 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 78 74016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74016 Reactome R-ALL-74016 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74016.3 COMPOUND C00076 1 Reactome Database ID Release 78 6814181 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814181 Reactome R-HSA-6814181 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814181.1 TGM5:Ca2+ Reactome DB_ID: 6814186 1 TGM5 Protein-glutamine gamma-glutamyltransferase 5 ecNumber2.3.2.13/ecNumber TGM5_HUMAN Reactome DB_ID: 6814176 UniProt:O43548 TGM5 TGM5 TGMX FUNCTION Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Contributes to the formation of the cornified cell envelope of keratinocytes.TISSUE SPECIFICITY Expressed in foreskin keratinocytes.INDUCTION By 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium in NHEK cells.SIMILARITY Belongs to the transglutaminase superfamily. Transglutaminase family. UniProt O43548 2 EQUAL 720 EQUAL Reactome Database ID Release 78 6814176 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814176 Reactome R-HSA-6814176 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814176.1 1 Reactome Database ID Release 78 6814186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814186 Reactome R-HSA-6814186 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814186.1 Reactome Database ID Release 78 6814175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814175 Reactome R-HSA-6814175 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814175.1 GENE ONTOLOGY GO:0003810 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 6814179 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814179 Reactome Database ID Release 78 6810894 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810894 Reactome R-HSA-6810894 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810894.1 6105840 Pubmed 1980 Transglutaminases Folk, JE Annu. Rev. Biochem. 49:517-31 10588656 Pubmed 1999 Initiation of assembly of the cell envelope barrier structure of stratified squamous epithelia Steinert, P M Marekov, L N Mol. Biol. Cell 10:4247-61 2461365 Pubmed 1988 The glutamine residues reactive in transglutaminase-catalyzed cross-linking of involucrin Simon, M Green, H J. Biol. Chem. 263:18093-8 73346 Pubmed 1977 The epsilon-(gamma-glutamyl)lysine crosslink and the catalytic role of transglutaminases Folk, JE Finlayson, J S Adv. Protein Chem. 31:1-133 10510474 Pubmed 1999 Transglutaminase crosslinking and structural studies of the human small proline rich 3 protein Steinert, P M Candi, E Tarcsa, E Marekov, L N Sette, M Paci, M Ciani, B Guerrieri, P Melino, G Cell Death Differ. 6:916-30 LEFT-TO-RIGHT Membrane proteases cleave Profilaggrin producing Filaggrin Filaggrin is initially synthesized as a large, insoluble, highly phosphorylated precursor containing many tandem copies of 324 residues. This precursor is dephosphorylated and proteolytically cleaved by several proteases, including the undefined protease PEP1 (Resing et al. 1996), mu-calpain (Yamazaki et al. 1997), furin, PCSK6 (PACE4) (Pearton et al. 2001), PRSS8 (cap1) (Leyvraz et al. 2005), ST14 (matriptase) (List et al. 2003), CELA2 (Bonnart et al. 2010), CASP14 (Denecker et al. 2007) and Kallikrein-related peptidase 5 (KLK5) (Sakabe et al. 2013). Filaggrin is further processed and proteolytically degraded by CASP14 (Eckhart & Tschachler 2011). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 FILA_HUMAN FLG(1-4061) Profilaggrin Reactome DB_ID: 8849818 UniProt:P20930 FLG FLG FUNCTION Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.TISSUE SPECIFICITY Expressed in skin, thymus, stomach, tonsils, testis, placenta, kidney, pancreas, mammary gland, bladder, thyroid, salivary gland and trachea, but not detected in heart, brain, liver, lung, bone marrow, small intestine, spleen, prostate, colon, or adrenal gland (PubMed:19384417). In the skin, mainly expressed in stratum granulosum of the epidermis (PubMed:1429717) (PubMed:19384417).INDUCTION In cultured foreskin fibroblasts, up-regulated in response to Ca(2+) stimulation.PTM Filaggrin is initially synthesized as a large, insoluble, highly phosphorylated precursor containing many tandem copies of 324 AA, which are not separated by large linker sequences. During terminal differentiation it is dephosphorylated and proteolytically cleaved. The N-terminal of the mature protein is heterogeneous, and is blocked by the formation of pyroglutamate.PTM Undergoes deimination of some arginine residues (citrullination).SIMILARITY Belongs to the S100-fused protein family. UniProt P20930 1 EQUAL 4061 EQUAL Reactome Database ID Release 78 8849818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849818 Reactome R-HSA-8849818 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849818.1 FLG(?-?) Filaggrin FILA_HUMAN Reactome DB_ID: 6810859 Reactome Database ID Release 78 6810859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810859 Reactome R-HSA-6810859 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810859.1 ACTIVATION Converted from EntitySet in Reactome Membrane profilaggrin processing proteases Reactome DB_ID: 8849785 FURIN Furin Reactome DB_ID: 2159856 UniProt:P09958 FURIN FURIN FUR PACE PCSK3 FUNCTION Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (PubMed:11799113, PubMed:1629222, PubMed:1713771, PubMed:2251280, PubMed:24666235, PubMed:25974265, PubMed:7592877, PubMed:7690548, PubMed:9130696). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (PubMed:7737999). Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-32) (PubMed:20489134, PubMed:21763278).FUNCTION (Microbial infection) Cleaves and activates diphtheria toxin DT.FUNCTION (Microbial infection) Cleaves and activates anthrax toxin protective antigen (PA).FUNCTION (Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin.FUNCTION (Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP.FUNCTION (Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells.ACTIVITY REGULATION Inhibited by the not secondly cleaved propeptide (PubMed:9130696, PubMed:11799113). Inhibited by m-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)-benzamidine (m-guanidinomethyl-Phac-RVR-Amb) and 4-guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) (PubMed:24666235, PubMed:25974265). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl-RVKR-CMK) (PubMed:32362314).SUBUNIT Interacts with FLNA (By similarity). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (PubMed:11331585).TISSUE SPECIFICITY Seems to be expressed ubiquitously.DOMAIN Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface.PTM The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation.PTM Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms.SIMILARITY Belongs to the peptidase S8 family. Furin subfamily. UniProt P09958 108 EQUAL 794 EQUAL Reactome Database ID Release 78 2159856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2159856 Reactome R-HSA-2159856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2159856.1 PCSK6 PACE4 (PCSK6) Proprotein convertase subtilisin/kexin type 6 PCSK6_HUMAN Reactome DB_ID: 8849792 UniProt:P29122 PCSK6 PCSK6 PACE4 FUNCTION Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive secretory pathway, with unique restricted distribution in both neuroendocrine and non-neuroendocrine tissues.SUBUNIT The PACE4A-I precursor protein seems to exist in the reticulum endoplasmic as both a monomer and a dimer-sized complex whereas mature PACE4A-I exists only as a monomer, suggesting that propeptide cleavage affects its tertiary or quaternary structure. Interacts (immature form including the propeptide) with RCN3; probably involved in the maturation and the secretion of PCSK6 (PubMed:16433634).TISSUE SPECIFICITY Each PACE4 isoform exhibits a unique restricted distribution. Isoform PACE4A-I is expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, but at comparatively higher levels in the liver. Isoform PACE4A-II is at least expressed in placenta. Isoform PACE4B was only found in the embryonic kidney cell line from which it was isolated. Isoform PACE4C and isoform PACE4D are expressed in placenta. Isoform PACE4E-I is expressed in cerebellum, placenta and pituitary. Isoform PACE4E-II is at least present in cerebellum.DOMAIN The propeptide domain acts as an intramolecular chaperone assisting the folding of the zymogen within the endoplasmic reticulum. Isoform PACE4D lacks the propeptide domain.SIMILARITY Belongs to the peptidase S8 family. UniProt P29122 150 EQUAL 969 EQUAL Reactome Database ID Release 78 8849792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849792 Reactome R-HSA-8849792 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849792.1 ST14 Suppressor of tumorigenicity 14 protein Matriptase Reactome DB_ID: 8849787 UniProt:Q9Y5Y6 ST14 ST14 PRSS14 SNC19 TADG15 FUNCTION Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Involved in the terminal differentiation of keratinocytes through prostasin (PRSS8) activation and filaggrin (FLG) processing.SUBUNIT Interacts with CDCP1. May interact with TMEFF1.SIMILARITY Belongs to the peptidase S1 family. UniProt Q9Y5Y6 1 EQUAL 855 EQUAL Reactome Database ID Release 78 8849787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849787 Reactome R-HSA-8849787 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849787.1 PRSS8 Reactome DB_ID: 8849802 PRSS8_HUMAN PRSS8(33-44) Prostasin light chain Reactome DB_ID: 8849805 UniProt:Q16651 PRSS8 PRSS8 FUNCTION Possesses a trypsin-like cleavage specificity with a preference for poly-basic substrates. Stimulates epithelial sodium channel (ENaC) activity through activating cleavage of the gamma subunits (SCNN1G).SUBUNIT Heterodimer of two chains, light and heavy, held by a disulfide bond.TISSUE SPECIFICITY Found in prostate, liver, salivary gland, kidney, lung, pancreas, colon, bronchus and renal proximal tubular cells. In the prostate gland it may be synthesized in epithelial cells, secreted into the ducts, and excreted into the seminal fluid.SIMILARITY Belongs to the peptidase S1 family. UniProt Q16651 33 EQUAL 44 EQUAL Reactome Database ID Release 78 8849805 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849805 Reactome R-HSA-8849805 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849805.1 1 PRSS8_HUMAN PRSS8(45-322) Prostasin heavy chain Reactome DB_ID: 8849789 45 EQUAL 322 EQUAL Reactome Database ID Release 78 8849789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849789 Reactome R-HSA-8849789 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849789.1 1 Reactome Database ID Release 78 8849802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849802 Reactome R-HSA-8849802 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849802.1 Reactome Database ID Release 78 8849785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849785 Reactome R-HSA-8849785 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849785.1 GENE ONTOLOGY GO:0004175 Reactome Database ID Release 78 8849786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849786 Reactome Database ID Release 78 8849797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849797 Reactome R-HSA-8849797 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849797.2 17515931 Pubmed 2007 Caspase-14 protects against epidermal UVB photodamage and water loss Denecker, Geertrui Hoste, Esther Gilbert, Barbara Hochepied, Tino Ovaere, Petra Lippens, Saskia Van den Broecke, Caroline Van Damme, Petra D'Herde, Katharina Hachem, Jean-Pierre Borgonie, Gaetan Presland, Richard B Schoonjans, Luc Libert, Claude Vandekerckhove, Joël Gevaert, Kris Vandenabeele, P Declercq, Wim Nat. Cell Biol. 9:666-74 14638864 Pubmed 2003 Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1 List, Karin Szabo, Roman Wertz, Philip W Segre, Julie Haudenschild, Christian C Kim, Soo-Youl Bugge, Thomas H J. Cell Biol. 163:901-10 23629652 Pubmed 2013 Kallikrein-related peptidase 5 functions in proteolytic processing of profilaggrin in cultured human keratinocytes Sakabe, Jun-ichi Yamamoto, Mami Hirakawa, Satoshi Motoyama, Akira Ohta, Isao Tatsuno, Kazuki Ito, Taisuke Kabashima, Kenji Hibino, Toshihiko Tokura, Yoshiki J. Biol. Chem. 288:17179-89 20179351 Pubmed 2010 Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing Bonnart, Chrystelle Deraison, Celine Lacroix, Matthieu Uchida, Yoshikazu Besson, Celine Robin, Aurélie Briot, Anaïs Gonthier, Marie Lamant, Laurence Dubus, Pierre Monsarrat, Bernard Hovnanian, Alain J. Clin. Invest. 120:871-82 7499312 Pubmed 1995 Characterization of profilaggrin endoproteinase 1. A regulated cytoplasmic endoproteinase of epidermis Resing, K A Thulin, C Whiting, K al-Alawi, N Mostad, S J. Biol. Chem. 270:28193-8 16061697 Pubmed 2005 The epidermal barrier function is dependent on the serine protease CAP1/Prss8 Leyvraz, Céline Charles, Roch-Philippe Rubera, Isabelle Guitard, Marjorie Rotman, Samuel Breiden, Bernadette Sandhoff, K Hummler, Edith J. Cell Biol. 170:487-96 11380615 Pubmed 2001 Proprotein convertase expression and localization in epidermis: evidence for multiple roles and substrates Pearton, D J Nirunsuksiri, W Rehemtulla, A Lewis, S P Presland, R B Dale, B A Exp. Dermatol. 10:193-203 9207214 Pubmed 1997 Cytoplasmic processing of human profilaggrin by active mu-calpain Yamazaki, M Ishidoh, K Suga, Y Saido, T C Kawashima, S Suzuki, K Kominami, E Ogawa, H Biochem. Biophys. Res. Commun. 235:652-6 21997417 Pubmed 2011 Cuts by caspase-14 control the proteolysis of filaggrin Eckhart, Leopold Tschachler, Erwin J. Invest. Dermatol. 131:2173-5 LEFT-TO-RIGHT Cytoplasmic proteases cleave Profilaggrin producing Filaggrin Filaggrin is initially synthesized as a large, insoluble, highly phosphorylated precursor containing many tandem copies of 324 residues. This precursor is dephosphorylated and proteolytically cleaved by several proteases, including the undefined protease PEP1 (Resing et al. 1996), mu-calpain (Yamazaki et al. 1997), furin, PCSK6 (PACE4) (Pearton et al. 2001), PRSS8 (cap1) (Leyvraz et al. 2005), ST14 (matriptase) (List et al. 2003), CELA2 (Bonnart et al. 2010), CASP14 (Denecker et al. 2007) and Kallikrein-related peptidase 5 (KLK5) (Sakabe et al. 2013). Filaggrin is further processed and proteolytically degraded by CASP14 (Eckhart & Tschachler 2011). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 ACTIVATION Converted from EntitySet in Reactome Cytoplasmic profilaggrin processing proteases Reactome DB_ID: 8934797 Calpain1 CAPN1:CAPNS1:Ca2+ Reactome DB_ID: 3288241 4 CAPNS1 Calpain small subunit 1 CPNS1_HUMAN Reactome DB_ID: 3288229 UniProt:P04632 CAPNS1 CAPNS1 CAPN4 CAPNS FUNCTION Regulatory subunit of the calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.SUBUNIT Homodimer or heterodimer of a large (catalytic) and a small (regulatory) subunit. In presence of calcium, the heterodimer dissociates (By similarity).DOMAIN The contact of the 5th EF-hand domain from each monomer allows the formation of the homodimer and also appears to mediate the contact between the large catalytic subunit and small regulatory subunit for the formation of the heterodimer.DOMAIN EF-hand domains are paired. EF-hand 1 is paired with EF-hand 2 and EF-hand 3 is paired with EF-hand 4. The fifth EF-hand domain, left unpaired, does not bind the calcium but is responsible of the dimerization by EF-embrace. The first four EF-hand domains bind calcium, however it is not sure if the binding of EF-hand 4 to calcium is physiologically relevant. UniProt P04632 1 EQUAL 268 EQUAL Reactome Database ID Release 78 3288229 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3288229 Reactome R-HSA-3288229 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3288229.1 1 CAPN1 Calpain-1 catalytic subunit ecNumber3.4.22.52/ecNumber CAN1_HUMAN Reactome DB_ID: 3288367 UniProt:P07384 CAPN1 CAPN1 CANPL1 PIG30 FUNCTION Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction (PubMed:21531719, PubMed:2400579). Proteolytically cleaves CTBP1 at 'Asn-375', 'Gly-387' and 'His-409' (PubMed:23707407).ACTIVITY REGULATION Activated by micromolar concentrations of calcium and inhibited by calpastatin.SUBUNIT Forms a heterodimer with a small (regulatory) subunit CAPNS1.TISSUE SPECIFICITY Ubiquitous.PTM Undergoes calcium-induced successive autoproteolytic cleavages that generate a membrane-bound 78 kDa active form and an intracellular 75 kDa active form. Calpastatin reduces with high efficiency the transition from 78 kDa to 75 kDa calpain forms.SIMILARITY Belongs to the peptidase C2 family. UniProt P07384 1 EQUAL 714 EQUAL Reactome Database ID Release 78 3288367 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3288367 Reactome R-HSA-3288367 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3288367.1 1 Reactome Database ID Release 78 3288241 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3288241 Reactome R-HSA-3288241 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3288241.1 CASP14 Reactome DB_ID: 8847680 CASPE_HUMAN CASP14(153-242) Caspase-14 p10 subunit Reactome DB_ID: 8847687 UniProt:P31944 CASP14 CASP14 FUNCTION Non-apoptotic caspase involved in epidermal differentiation. Is the predominant caspase in epidermal stratum corneum (PubMed:15556625). Seems to play a role in keratinocyte differentiation and is required for cornification. Regulates maturation of the epidermis by proteolytically processing filaggrin (By similarity). In vitro has a preference for the substrate [WY]-X-X-D motif and is active on the synthetic caspase substrate WEHD-ACF (PubMed:16854378, PubMed:19960512). Involved in processing of prosaposin in the epidermis (By similarity). May be involved in retinal pigment epithelium cell barrier function (PubMed:25121097). Involved in DNA degradation in differentiated keratinocytes probably by cleaving DFFA/ICAD leading to liberation of DFFB/CAD (PubMed:24743736).ACTIVITY REGULATION Inhibited by caspase-1 inhibitor YVAD-FMK and the pan-caspase inhibitor VAD-FMK.SUBUNIT Heterodimer of a large and a small subunit, both processed from the precursor; the mature active form is a p17/p10 dimer and the intermediate form a p20/p8 dimer.TISSUE SPECIFICITY Expressed in keratinocytes of adult skin suprabasal layers (from spinous layers to the stratum granulosum and stratum corneum) (at protein level). Expressed in keratinocytes of hair shaft and sebaceous glands (at protein level). In psoriatic skin only expressed at very low levels (PubMed:11175259). The p17/10 mature form is expressed in epidermis stratum corneum, the p20/p8 intermediate form in epidermis upper granular cells of the stratum granulosum (PubMed:22825846).INDUCTION In undifferentiated keratinocytes under postconfluency growth conditions (in vitro) (PubMed:11175259). By high glucose in retinal pigment epithelia cells (PubMed:25121097).PTM Maturation by proteolytic processing appears to be a two-step process. The precursor is processed by KLK7 to yield the p20/p8 intermediate form which acts on the precursor to yield the p17/p10 mature form (PubMed:22825846). Initially, cleavage between Ile-152 and Lys-153 has been proposed to yield the large and small subunits of the active enzyme (PubMed:12200134).MISCELLANEOUS Expressed in bacteria requires high concentrations of kosmotropic salts to be activated (PubMed:15301553). The mature and the intermediate form differ in activity towards synthetic caspase substrates: the p17/p10 mature form but not the p20/p8 intermediate form is active on WEHD-MCA; p20/p8 is active on a number of other caspase substrates without any marked preference (VEID-AFC, DEVD-AFC, LEVD-AFC and LEHD-AFC) (PubMed:22825846).SIMILARITY Belongs to the peptidase C14A family. UniProt P31944 153 EQUAL 242 EQUAL Reactome Database ID Release 78 8847687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847687 Reactome R-HSA-8847687 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847687.1 1 CASPE_HUMAN CASP14(6-146) Caspase-14 p17 subunit Reactome DB_ID: 8847667 6 EQUAL 146 EQUAL Reactome Database ID Release 78 8847667 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847667 Reactome R-HSA-8847667 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847667.1 1 Reactome Database ID Release 78 8847680 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847680 Reactome R-HSA-8847680 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847680.1 KLK5 KLK5(67-293) Kallikrein-5 SCTE Stratum corneum tryptic enzyme Reactome DB_ID: 8934778 UniProt:Q9Y337 KLK5 KLK5 SCTE UNQ570/PRO1132 FUNCTION May be involved in desquamation.ACTIVITY REGULATION Inhibited by Zn2+.SUBUNIT Interacts with SPINK9.TISSUE SPECIFICITY Expressed in skin, breast, brain and testis. Expressed at the stratum granulosum of palmar skin.SIMILARITY Belongs to the peptidase S1 family. Kallikrein subfamily. UniProt Q9Y337 67 EQUAL 293 EQUAL Reactome Database ID Release 78 8934778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934778 Reactome R-HSA-8934778 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934778.1 ELA2A CELA2A Chymotrypsin-like elastase family member 2A Elastase 2A Reactome DB_ID: 8934818 UniProt:P08217 CELA2A CELA2A ELA2A FUNCTION Elastase that enhances insulin signaling and might have a physiologic role in cellular glucose metabolism. Circulates in plasma and reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity.SUBUNIT Interacts with CPA1. Interacts with SERPINA1 (PubMed:31358993).TISSUE SPECIFICITY Expressed in pancreas. Not detected in keratinocytes (PubMed:10620133). Detected in exocrine secretions of the pancreas (at protein level). Also expressed in a small fraction of cells in pancreatic islets, adrenal cortex, intestinal glands and colonic lymphoid follicles (at protein level) (PubMed:31358993). Detected in plasma (PubMed:31358993).SIMILARITY Belongs to the peptidase S1 family. Elastase subfamily. UniProt P08217 29 EQUAL 269 EQUAL Reactome Database ID Release 78 8934818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934818 Reactome R-HSA-8934818 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934818.1 Reactome Database ID Release 78 8934797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934797 Reactome R-HSA-8934797 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934797.1 Reactome Database ID Release 78 8934826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934826 Reactome Database ID Release 78 8934819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934819 Reactome R-HSA-8934819 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934819.2 LEFT-TO-RIGHT Filaggrin binds Keratin tonofilament:Desmosome During cornification, a network of keratin intermediate filaments (KIF) and filaggrin (FLG) becomes crosslinked to the cornified envelope (CE). The FLG-KIF linkage occurs primarily through a specific lysine residue on the head domain of type II keratin chains, which can crosslink with several CE proteins including loricrin, SPRs, envoplakin and involucrin (Dale et al. 1978, Manabe et al. 1991, Mack et al. 1993, Steinert et al. 1995, Candi et al. 1998). This FLG-KIF crosslinking is believed to organise intermediate filaments into bundles, which stabilize the keratin network (Steinert et al. 1981, Candi et al. 2005) and facilitate the collapse and flattening of cells in the outermost stratum corneum to produce squames. Cell flattening can occur in the absence of FLG, but at the ultrastructural level loss-of-function mutations in FLG are associated with disorganized keratin filaments, impaired lamellar body loading and abnormal architecture of the lamellar bilayer (Gruber et al. 2011). Authored: Jupe, Steve, 2016-09-23 Reviewed: Blumenberg, Miroslav, 2016-08-12 Keratin tonofilament:Desmosome Reactome DB_ID: 6814735 Desmosome Reactome DB_ID: 6814388 JUP Junction plakoglobin PLAK_HUMAN Reactome DB_ID: 437260 UniProt:P14923 JUP JUP CTNNG DP3 FUNCTION Common junctional plaque protein. The membrane-associated plaques are architectural elements in an important strategic position to influence the arrangement and function of both the cytoskeleton and the cells within the tissue. The presence of plakoglobin in both the desmosomes and in the intermediate junctions suggests that it plays a central role in the structure and function of submembranous plaques. Acts as a substrate for VE-PTP and is required by it to stimulate VE-cadherin function in endothelial cells. Can replace beta-catenin in E-cadherin/catenin adhesion complexes which are proposed to couple cadherins to the actin cytoskeleton (By similarity).SUBUNIT Homodimer. Component of an E-cadherin/catenin adhesion complex composed of at least E-cadherin/CDH1 and gamma-catenin/JUP, and possibly alpha-catenin/CTNNA1; the complex is located to adherens junctions. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Interacts with MUC1. Interacts with CAV1 (By similarity). Interacts with PTPRJ. Interacts with DSG1. Interacts with DSC1 and DSC2. Interacts with PKP2.DOMAIN The entire ARM repeats region mediates binding to CDH1/E-cadherin. The N-terminus and first three ARM repeats are sufficient for binding to DSG1. The N-terminus and first ARM repeat are sufficient for association with CTNNA1. DSC1 association requires both ends of the ARM repeat region.PTM May be phosphorylated by FER.SIMILARITY Belongs to the beta-catenin family. UniProt P14923 1 EQUAL 745 EQUAL Reactome Database ID Release 78 437260 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437260 Reactome R-HSA-437260 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-437260.1 1 Converted from EntitySet in Reactome Plakophilins Reactome DB_ID: 6814720 PKP1 Plakophilin 1 Reactome DB_ID: 201597 UniProt:Q13835 PKP1 PKP1 FUNCTION Seems to play a role in junctional plaques. Contributes to epidermal morphogenesis.TISSUE SPECIFICITY Isoform 2 is widely expressed. Isoform 1 is expressed in stratified squamous, complex, glandular duct and bladder epithelia.SIMILARITY Belongs to the beta-catenin family. UniProt Q13835 1 EQUAL 747 EQUAL Reactome Database ID Release 78 201597 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201597 Reactome R-HSA-201597 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201597.1 PKP2 Plakophilin-2 PKP2_HUMAN Reactome DB_ID: 6814393 UniProt:Q99959 PKP2 PKP2 FUNCTION May play a role in junctional plaques.SUBUNIT Interacts with DSC2. Interacts with JUP and desmoplakin/DSP.TISSUE SPECIFICITY Detected in heart right ventricle (at protein level). Widely expressed. Found at desmosomal plaques in simple and stratified epithelia and in non-epithelial tissues such as myocardium and lymph node follicles. In most stratified epithelia found in the desmosomes of the basal cell layer and seems to be absent from suprabasal strata.SIMILARITY Belongs to the beta-catenin family. UniProt Q99959 1 EQUAL 881 EQUAL Reactome Database ID Release 78 6814393 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814393 Reactome R-HSA-6814393 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814393.1 PKP3 Plakophilin-3 PKP3_HUMAN Reactome DB_ID: 6814399 UniProt:Q9Y446 PKP3 PKP3 FUNCTION May play a role in junctional plaques.TISSUE SPECIFICITY Isoform PKP3a is found in desmosomes of most simple and stratified epithelia. Not found in foreskin fibroblasts and various sarcoma-derived cell lines. Beside dendritic reticular cells of lymphatic follicles not found in non-epithelial desmosome-bearing tissues. Isoform PKP3b is abundant in the desmosomes of stratified epithelial cell but absent in simple epithelial cells, it is also expressed in the colon and its tumors.SIMILARITY Belongs to the beta-catenin family. UniProt Q9Y446 1 EQUAL 797 EQUAL Reactome Database ID Release 78 6814399 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814399 Reactome R-HSA-6814399 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814399.1 PKP4 Plakophilin-4 PKP4_HUMAN Reactome DB_ID: 6814401 UniProt:Q99569 PKP4 PKP4 FUNCTION Plays a role as a regulator of Rho activity during cytokinesis. May play a role in junctional plaques.SUBUNIT Interacts with PDZD2 (By similarity). Interacts (via the C-terminus) with FRMPD2 (via the PDZ 2 domain). Interacts with RHOA; the interaction is detected at the midbody. Interacts with ECT2; the interaction is detected at the midbody. Interacts with CCDC85B (PubMed:25009281).SIMILARITY Belongs to the beta-catenin family. UniProt Q99569 1 EQUAL 1192 EQUAL Reactome Database ID Release 78 6814401 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814401 Reactome R-HSA-6814401 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814401.1 Reactome Database ID Release 78 6814720 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814720 Reactome R-HSA-6814720 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814720.1 1 DSP Desmoplakin Reactome DB_ID: 201580 UniProt:P15924 DSP DSP FUNCTION Major high molecular weight protein of desmosomes. Involved in the organization of the desmosomal cadherin-plakoglobin complexes into discrete plasma membrane domains and in the anchoring of intermediate filaments to the desmosomes.SUBUNIT Homodimer. Interacts with COL17A1 (via cytoplasmic region). Associates (via C-terminal) with KRT5-KRT14 (via rod region), KRT8-KRT18 and VIM intermediate filaments. Interacts with DSC2. Interacts with PKP2. Interacts weakly with TMEM65 (By similarity).TISSUE SPECIFICITY Isoform DPI is apparently an obligate constituent of all desmosomes. Isoform DPII resides predominantly in tissues and cells of stratified origin.DOMAIN Its association with epidermal and simple keratins is dependent on the tertiary structure induced by heterodimerization of these intermediate filaments proteins and most likely involves recognition sites located in the rod domain of these keratins.DOMAIN The N-terminal region is required for localization to the desmosomal plaque and interacts with the N-terminal region of plakophilin 1.DOMAIN The three tandem plakin repeat regions in the C-terminus mediate binding to intermediate filaments.PTM Ser-2849 is probably phosphorylated by a cAMP-dependent protein kinase. Phosphorylation on Ser-2849 probably affects its association with epidermal, simple cytokeratins and VIM intermediate filaments.SIMILARITY Belongs to the plakin or cytolinker family. UniProt P15924 1 EQUAL 2871 EQUAL Reactome Database ID Release 78 201580 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201580 Reactome R-HSA-201580 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201580.1 1 Converted from EntitySet in Reactome Desmocolins Reactome DB_ID: 6814733 DSC1 Desmocollin-1 DSC1_HUMAN Reactome DB_ID: 6801533 UniProt:Q08554 DSC1 DSC1 CDHF1 FUNCTION Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms. Linked to the keratinization of epithelial tissues.SUBUNIT Binds to JUP/plakoglobin.TISSUE SPECIFICITY Strongly expressed in epidermis, less in lymph node and tongue.DOMAIN Calcium may be bound by the cadherin-like repeats.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain. UniProt Q08554 135 EQUAL 894 EQUAL Reactome Database ID Release 78 6801533 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6801533 Reactome R-HSA-6801533 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6801533.1 DSC2 Desmocollin-2 DSC2_HUMAN Reactome DB_ID: 6814398 UniProt:Q02487 DSC2 DSC2 CDHF2 DSC3 FUNCTION Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms.SUBUNIT Interacts with DSP, PKP2 and JUP.TISSUE SPECIFICITY Expressed in epithelia, myocardium and lymph nodes.DOMAIN Calcium may be bound by the cadherin-like repeats.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain. UniProt Q02487 136 EQUAL 901 EQUAL Reactome Database ID Release 78 6814398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814398 Reactome R-HSA-6814398 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814398.1 DSC3 Desmocollin 3 Reactome DB_ID: 6814396 UniProt:Q14574 DSC3 DSC3 CDHF3 DSC4 FUNCTION Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms.TISSUE SPECIFICITY Epidermis, buccal mucosa, esophagus and cervix.DOMAIN Calcium may be bound by the cadherin-like repeats.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain. UniProt Q14574 136 EQUAL 896 EQUAL Reactome Database ID Release 78 6814396 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814396 Reactome R-HSA-6814396 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814396.1 Reactome Database ID Release 78 6814733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814733 Reactome R-HSA-6814733 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814733.1 1 Converted from EntitySet in Reactome Desmogelins Reactome DB_ID: 6814694 DSG1 Desmoglein 1 Reactome DB_ID: 202912 UniProt:Q02413 DSG1 DSG1 CDHF4 FUNCTION Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.SUBUNIT Binds to JUP/plakoglobin.SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus protein SdrD; this interaction increases S. aureus adherence to keratinocytes.TISSUE SPECIFICITY Epidermis, tongue, tonsil and esophagus.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain. UniProt Q02413 50 EQUAL 1049 EQUAL Reactome Database ID Release 78 202912 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202912 Reactome R-HSA-202912 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202912.1 DSG2 Desmoglein 2 Reactome DB_ID: 351896 UniProt:Q14126 DSG2 DSG2 CDHF5 FUNCTION Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.TISSUE SPECIFICITY All of the tissues tested and carcinomas.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain. UniProt Q14126 50 EQUAL 1118 EQUAL Reactome Database ID Release 78 351896 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351896 Reactome R-HSA-351896 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351896.1 DSG3 Desmoglein 3 Reactome DB_ID: 201590 UniProt:P32926 DSG3 DSG3 CDHF6 FUNCTION Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.TISSUE SPECIFICITY Epidermis, tongue, tonsil, esophagus and carcinomas.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain.MISCELLANEOUS Pemphigus vulgaris (PV) is a potentially lethal skin disease in which epidermal blisters occur as the result of the loss of cell-cell adhesion caused by the action of autoantibodies against desmoglein 3. UniProt P32926 50 EQUAL 999 EQUAL Reactome Database ID Release 78 201590 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201590 Reactome R-HSA-201590 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201590.1 DSG4 Desmoglein-4 DSG4_HUMAN Reactome DB_ID: 6814743 UniProt:Q86SJ6 DSG4 DSG4 CDHF13 FUNCTION Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. Coordinates the transition from proliferation to differentiation in hair follicle keratinocytes (By similarity).TISSUE SPECIFICITY Highly expressed in skin, testis and prostate; less in salivary gland. In scalp follicles, present in the inner root sheath (IRS) and all layers of the matrix and precortex.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain.DISEASE Autoantibodies against DSG4 are found in patients with pemphigus vulgaris. Pemphigus vulgaris is a potentially lethal skin disease in which epidermal blisters occur as the result of the loss of cell-cell adhesion. UniProt Q86SJ6 50 EQUAL 1040 EQUAL Reactome Database ID Release 78 6814743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814743 Reactome R-HSA-6814743 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814743.1 Reactome Database ID Release 78 6814694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814694 Reactome R-HSA-6814694 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814694.1 1 Reactome Database ID Release 78 6814388 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814388 Reactome R-HSA-6814388 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814388.2 1 Keratin tonofilament Reactome DB_ID: 6809668 Reactome Database ID Release 78 6809668 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809668 Reactome R-HSA-6809668 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6809668.2 ChEBI 36080 1 Reactome Database ID Release 78 6814735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814735 Reactome R-HSA-6814735 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814735.2 FLG(?-?):Keratin tonofilament:Desmosome Reactome DB_ID: 8942225 1 1 Reactome Database ID Release 78 8942225 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942225 Reactome R-HSA-8942225 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942225.1 Reactome Database ID Release 78 8942224 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942224 Reactome R-HSA-8942224 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942224.1 9482839 Pubmed 1998 A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases Candi, E Tarcsa, E Digiovanna, J J Compton, J G Elias, P M Marekov, L N Steinert, P M Proc. Natl. Acad. Sci. U.S.A. 95:2067-72 732879 Pubmed 1978 Assembly of stratum corneum basic protein and keratin filaments in macrofibrils Dale, B A Holbrook, K A Steinert, P M Nature 276:729-31 7543090 Pubmed 1995 The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope Steinert, P M Marekov, L N J. Biol. Chem. 270:17702-11 21514438 Pubmed 2011 Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function Gruber, Robert Elias, Peter M Crumrine, Debra Lin, Tzu-Kai Brandner, Johanna M Hachem, Jean-Pierre Presland, Richard B Fleckman, Philip Janecke, Andreas R Sandilands, Aileen McLean, W H Irwin Fritsch, Peter O Mildner, Michael Tschachler, Erwin Schmuth, Matthias Am. J. Pathol. 178:2252-63 7687298 Pubmed 1993 The mechanism of interaction of filaggrin with intermediate filaments. The ionic zipper hypothesis Mack, J W Steven, A C Steinert, P M J. Mol. Biol. 232:50-66 1720750 Pubmed 1991 Interaction of filaggrin with keratin filaments during advanced stages of normal human epidermal differentiation and in ichthyosis vulgaris Manabe, M Sanchez, M Sun, T T Dale, B A Differentiation 48:43-50 6170061 Pubmed 1981 Characterization of a class of cationic proteins that specifically interact with intermediate filaments Steinert, P M Cantieri, J S Teller, DC Lonsdale-Eccles, J D Dale, B A Proc. Natl. Acad. Sci. U.S.A. 78:4097-101 LEFT-TO-RIGHT Fillagrin and keratin intermediate filaments polymerise forming a network During cornification a network of keratin intermediate filaments (KIF) and filaggrin (FLG) becomes crosslinked to the cornified envelope (CE). This facilitates the collapse and flattening of cells in the outermost stratum corneum to produce squames (Dale et al. 1978, Mack et al. 1993, Candi et al. 2005, Gruber et al. 2011). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 FLG-Keratin filament network Reactome DB_ID: 6814323 Reactome Database ID Release 78 6814323 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814323 Reactome R-HSA-6814323 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814323.3 ChEBI 36080 Reactome Database ID Release 78 6810357 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810357 Reactome R-HSA-6810357 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810357.2 LEFT-TO-RIGHT Reinforcement of the Cornified Envelope The inital scaffold of the cornified envelope (CE) is reinforced by the inclusion of loricrin (LOR) and small proline-rich proteins (SPRs), which together comprise about 75% of the total mass of the CE. Other proteins include filaggrin (FLG) (8%), elafin (6%), cystatin A (5%), involucrin (IVL) and keratin intermediate filaments (KIFs) (about 2% each) (Steinert & Marekov 1995). Other minor proteins include repetin (RPTN), trichohyalin (TCHH) and elafin (PI3) (Steinert & Marekov 1997, Steinert et al. 1998). <br><br>LOR is poorly soluble in vivo, while SPRs are very soluble. Both are preferred substrates of cytosolic transglutaminase-3 (TGM3) (Candi et al. 1999, Steinert et al. 1999, Tarcsa et al. 1999), which suggests that TGM3 may cross-link LOR and SPRs to create soluble complexes that are more easily translocated to the cell periphery (Kalinin et al. 2002). These cross-linked oligomers are good substrates for TGM1 (Candi et al. 1999, Steinert et al. 1999) which may link the LOR-SPR complexes to the CE scaffold. LOR can also be crosslinked by TGM5 (Candi et al. 2001). SPR content varies in epithelia from different body sites and increasing SPR content correlates with mechanical requirements of the tissue (Steinert et al. 1998). In humans LOR is initially deposited in the granular layer of the epidermis in keratohyalin granules, intermixed with profilaggrin (Yoneda & Steinert 1993). These are encoded in a linked 'Epidermal Differentiation Complex.' (Kypriotou et al. 2012, Niehues et al. 2016).<br><br>As the main component of the CE (Steinert & Marekov 1995), LOR is thought to function as the main reinforcement protein. LOR proteins are extensively crosslinked through isopeptide bonds but also crosslinked to SPRs, which may function as bridging proteins between LOR molecules (Candi et al. 2005). LOR can also form crosslinks with keratin and filaggrin (Steinert & Marekov 1995). CE crosslinking involves TGM1, TGM3 and TGM5 (Lorand & Graham 2003). The type-II keratin chains (K1, K2e and K5) are crosslinked at a specific Lys residue that is located in a conserved region of the V1 subdomain of the head domain (Steinert & Marekov 1995). IVL can be crosslinked by TGM1, which preferentially crosslinks Gln495 and Gln496 (Simon & Green 1998). In vitro, LOR is a substrate for TGM1-3 and 5 (Candi et al. 1995). In the epidermis, TGM1, TGM5 and TGM3 are believed to crosslink LOR sequentially; an initial attachment by TGM1 and 5 forms interchain crosslinks followed by a compaction process that involves TGM3 (Candi et al. 2005). SPRs are also TGM substrates, particularly TGM3 (Candi et al. 1999, Tarcsa et al. 1998, Steinert et al. 1999). <br><br>FLG binds KIFs, aggregating them into tight bundles. As a component of the CE, FLG 'glues' KIFs to the CE and coordinates the structure of cornifying cells (Steinert & Marekov 1995, Candi et al. 2005). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-10 Converted from EntitySet in Reactome SPRs Reactome DB_ID: 6810840 SPRR1A Cornifin-A SPR1A_HUMAN Reactome DB_ID: 6810862 UniProt:P35321 SPRR1A SPRR1A FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane.INDUCTION During squamous differentiation of epidermal keratinocytes.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt P35321 1 EQUAL 89 EQUAL Reactome Database ID Release 78 6810862 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810862 Reactome R-HSA-6810862 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810862.1 SPRR1B Cornifin-B SPR1B_HUMAN Reactome DB_ID: 6810855 UniProt:P22528 SPRR1B SPRR1B FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane. Can function as both amine donor and acceptor in transglutaminase-mediated cross-linkage.TISSUE SPECIFICITY Suprabasal layers of squamous-differentiated tissues such as epidermis, esophagus, tongue and trachea.DEVELOPMENTAL STAGE Expressed during differentiation of squamous cells.INDUCTION By carcinogenic agents and by UV light. During squamous differentiation of epidermal keratinocytes.PTM The N-terminus is blocked.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt P22528 1 EQUAL 89 EQUAL Reactome Database ID Release 78 6810855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810855 Reactome R-HSA-6810855 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810855.1 SPRR2A Small proline-rich protein 2A SPR2A_HUMAN Reactome DB_ID: 6810863 UniProt:P35326 SPRR2A SPRR2A FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane.INDUCTION During squamous differentiation of epidermal keratinocytes.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt P35326 1 EQUAL 72 EQUAL Reactome Database ID Release 78 6810863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810863 Reactome R-HSA-6810863 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810863.1 SPRR2B Small proline-rich protein 2B SPR2B_HUMAN Reactome DB_ID: 6810856 UniProt:P35325 SPRR2B SPRR2B FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane.TISSUE SPECIFICITY Suprabasal layers of squamous-differentiated tissues such as epidermis, esophagus, tongue and trachea.DEVELOPMENTAL STAGE Expressed during differentiation of squamous cells.INDUCTION By UV irradiation and carcinogenic agents. During squamous differentiation of epidermal keratinocytes.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt P35325 1 EQUAL 72 EQUAL Reactome Database ID Release 78 6810856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810856 Reactome R-HSA-6810856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810856.1 SPRR2D Small proline-rich protein 2D SPR2D_HUMAN Reactome DB_ID: 6810849 UniProt:P22532 SPRR2D SPRR2D FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane.INDUCTION During squamous differentiation of epidermal keratinocytes.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt P22532 1 EQUAL 72 EQUAL Reactome Database ID Release 78 6810849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810849 Reactome R-HSA-6810849 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810849.1 SPRR2E Small proline-rich protein 2E SPR2E_HUMAN Reactome DB_ID: 6810839 UniProt:P22531 SPRR2E SPRR2E FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane.INDUCTION During squamous differentiation of epidermal keratinocytes.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt P22531 1 EQUAL 72 EQUAL Reactome Database ID Release 78 6810839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810839 Reactome R-HSA-6810839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810839.1 SPRR2F Small proline-rich protein 2F SPR2F_HUMAN Reactome DB_ID: 6810858 UniProt:Q96RM1 SPRR2F SPRR2F FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane (By similarity).INDUCTION During squamous differentiation of epidermal keratinocytes.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt Q96RM1 1 EQUAL 72 EQUAL Reactome Database ID Release 78 6810858 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810858 Reactome R-HSA-6810858 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810858.1 SPRR2G Small proline-rich protein 2G SPR2G_HUMAN Reactome DB_ID: 6810846 UniProt:Q9BYE4 SPRR2G SPRR2G FUNCTION Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane (By similarity).INDUCTION During squamous differentiation of epidermal keratinocytes.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt Q9BYE4 1 EQUAL 73 EQUAL Reactome Database ID Release 78 6810846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810846 Reactome R-HSA-6810846 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810846.1 SPRR3 Small proline-rich protein 3 SPRR3_HUMAN Reactome DB_ID: 6810838 UniProt:Q9UBC9 SPRR3 SPRR3 SPRC FUNCTION Cross-linked envelope protein of keratinocytes.INDUCTION During squamous differentiation of epidermal keratinocytes.MASS SPECTROMETRY Variants Del 98-Cys--Pro-105 and Val-149.SIMILARITY Belongs to the cornifin (SPRR) family. UniProt Q9UBC9 2 EQUAL 169 EQUAL Reactome Database ID Release 78 6810838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810838 Reactome R-HSA-6810838 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810838.1 Reactome Database ID Release 78 6810840 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810840 Reactome R-HSA-6810840 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810840.1 LOR LORICRIN Loricrin LORI_HUMAN Reactome DB_ID: 6810848 UniProt:P23490 LORICRIN LORICRIN LOR LRN FUNCTION Major keratinocyte cell envelope protein.PTM Substrate of transglutaminases. Some glutamines and lysines are cross-linked to other loricrin molecules and to SPRRs proteins.PTM Contains inter- or intramolecular disulfide-bonds. UniProt P23490 1 EQUAL 312 EQUAL Reactome Database ID Release 78 6810848 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810848 Reactome R-HSA-6810848 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810848.2 Converted from EntitySet in Reactome Minor CE proteins Reactome DB_ID: 6814197 RPTN Repetin RPTN_HUMAN Reactome DB_ID: 6814185 UniProt:Q6XPR3 RPTN RPTN FUNCTION Involved in the cornified cell envelope formation. Multifunctional epidermal matrix protein. Reversibly binds calcium.TISSUE SPECIFICITY Expression is scattered in the normal epidermis but strong in the acrosyringium, the inner hair root sheath and in the filiform papilli of the tongue.DOMAIN Can be divided into a N-terminal domain with significant homology to S100-like calcium-binding proteins, a central domain containing a series of short tandem repeats, and two flanking segments with low homology to the consensus sequences of the central repeats.PTM Potential substrate of transglutaminase. Some arginines are probably converted to citrullines by peptidylarginine deimidase.SIMILARITY Belongs to the S100-fused protein family. UniProt Q6XPR3 1 EQUAL 784 EQUAL Reactome Database ID Release 78 6814185 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814185 Reactome R-HSA-6814185 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814185.1 TCHH Trichohyalin TRHY_HUMAN Reactome DB_ID: 6810842 UniProt:Q07283 TCHH TCHH THH THL TRHY FUNCTION Intermediate filament-associated protein that associates in regular arrays with keratin intermediate filaments (KIF) of the inner root sheath cells of the hair follicle and the granular layer of the epidermis. It later becomes cross-linked to KIF by isodipeptide bonds. It may serve as scaffold protein, together with involucrin, in the organization of the cell envelope or even anchor the cell envelope to the KIF network. It may be involved in its own calcium-dependent postsynthetic processing during terminal differentiation.SUBUNIT Monomer.TISSUE SPECIFICITY Found in the hard keratinizing tissues such as the inner root sheath (IRS) of hair follicles and medulla, and in the filiform papillae of dorsal tongue epithelium.DEVELOPMENTAL STAGE Expressed during late differentiation of the epidermis.DOMAIN Consists of nine domains. Domain 1 contains two EF-hand calcium-binding domains. Domains 2-4, 6, and 8 are almost entirely alpha-helical, configured as a series of peptide repeats of varying regularity, and are thought to form a single-stranded alpha-helical rod stabilized by ionic interactions. Domain 6 is the most regular and may bind KIF directly by ionic interactions. Domains 5 and 7 are less well organized and may induce folds in the molecule. Domain 9 contains the C-terminus, conserved among different species.PTM Substrate of transglutaminase. Some 200 arginines are probably converted to citrullines by peptidylarginine deimidase.SIMILARITY Belongs to the S100-fused protein family. UniProt Q07283 1 EQUAL 1943 EQUAL Reactome Database ID Release 78 6810842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810842 Reactome R-HSA-6810842 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810842.1 CSTA Cystatin-A CYTA_HUMAN Reactome DB_ID: 6814194 UniProt:P01040 CSTA CSTA STF1 STFA FUNCTION This is an intracellular thiol proteinase inhibitor. Has an important role in desmosome-mediated cell-cell adhesion in the lower levels of the epidermis.TISSUE SPECIFICITY Expressed in the skin throughout the epidermis.SIMILARITY Belongs to the cystatin family. UniProt P01040 1 EQUAL 98 EQUAL Reactome Database ID Release 78 6814194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814194 Reactome R-HSA-6814194 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814194.1 SKALP PI3(61-117) Peptidase inhibitor 3 Elafin Elastase-specific inhibitor Skin-derived antileukoproteinase WAP four-disulfide core domain protein 14 Protease inhibitor WAP3 Reactome DB_ID: 6814198 UniProt:P19957 PI3 PI3 WAP3 WFDC14 FUNCTION Neutrophil and pancreatic elastase-specific inhibitor of skin. It may prevent elastase-mediated tissue proteolysis. Has been shown to inhibit the alpha-4-beta-2/CHRNA2-CHRNB2 nicotinic acetylcholine receptor and to produce a weak inhibition on Kv11.1/KCNH2/ERG1 and on the transient receptor potential cation channel subfamily V member 1 (TRPV1) (PubMed:29483648).DOMAIN Consists of two domains: the transglutaminase substrate domain (cementoin moiety) and the elastase inhibitor domain. The transglutaminase substrate domain serves as an anchor to localize elafin covalently to specific sites on extracellular matrix proteins. UniProt P19957 61 EQUAL 117 EQUAL Reactome Database ID Release 78 6814198 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814198 Reactome R-HSA-6814198 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814198.1 Reactome Database ID Release 78 6814197 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814197 Reactome R-HSA-6814197 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814197.1 Early cornified envelope Reactome DB_ID: 6814285 1 1 1 1 1 Reactome Database ID Release 78 6814285 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814285 Reactome R-HSA-6814285 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814285.1 Reactome Database ID Release 78 6811539 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6811539 Reactome R-HSA-6811539 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6811539.1 22507538 Pubmed 2012 The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the 'fused genes' family Kypriotou, Magdalini Huber, Marcel Hohl, D Exp. Dermatol. 21:643-9 26556599 Pubmed 2016 Late cornified envelope (LCE) proteins: distinct expression patterns of LCE2 and LCE3 members suggest nonredundant roles in human epidermis and other epithelia Niehues, H van Vlijmen-Willems, I M J J Bergboer, J G M Kersten, F F J Narita, M Hendriks, W J A J van den Bogaard, E H Zeeuwen, P L J M Schalkwijk, J Br. J. Dermatol. 174:795-802 10066784 Pubmed 1999 Transglutaminase cross-linking properties of the small proline-rich 1 family of cornified cell envelope proteins. Integration with loricrin Candi, E Tarcsa, E Idler, W W Kartasova, T Marekov, L N Steinert, P M J. Biol. Chem. 274:7226-37 9722562 Pubmed 1998 Structural and transglutaminase substrate properties of the small proline-rich 2 family of cornified cell envelope proteins Tarcsa, E Candi, E Kartasova, T Idler, W W Marekov, L N Steinert, P M J. Biol. Chem. 273:23297-303 9565599 Pubmed 1998 Biochemical evidence that small proline-rich proteins and trichohyalin function in epithelia by modulation of the biomechanical properties of their cornified cell envelopes Steinert, P M Kartasova, T Marekov, L N J. Biol. Chem. 273:11758-69 8248167 Pubmed 1993 Overexpression of human loricrin in transgenic mice produces a normal phenotype Yoneda, K Steinert, P M Proc. Natl. Acad. Sci. U.S.A. 90:10754-8 7592852 Pubmed 1995 Biochemical, structural, and transglutaminase substrate properties of human loricrin, the major epidermal cornified cell envelope protein Candi, E Melino, G Mei, G Tarcsa, E Chung, S I Marekov, L N Steinert, P M J. Biol. Chem. 270:26382-90 12563291 Pubmed 2003 Transglutaminases: crosslinking enzymes with pleiotropic functions Lorand, Laszlo Graham, Robert M Nat. Rev. Mol. Cell Biol. 4:140-56 8999895 Pubmed 1997 Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope Steinert, P M Marekov, L N J. Biol. Chem. 272:2021-30 LEFT-TO-RIGHT Lamellar bodies bind the early cornified envelope Lamellar bodies (LBs) ) are lipid-rich organelles produced by keratinocytes and secreted to form an impermeable water barrier (Feingold & Elias 2014). The lipids in LBs contain phospholipids, glucosylceramides, sphingomyelin and cholesterol (Feingold 2007). These lipids, some of which are keratinization specific, are synthesized and accumulate in the trans Golgi apparatus, budding off as LBs that accumulate in the granular layer (Wertz & van den Bergh 1998). ). LB lipids also organize into characteristic intercellular lamellae (Kalinin et al. 2002). LBs fuse with the plasma membrane (Schmitz & Muller 1991, Chattopadhyay et al. 2003) delivering lipids which become ester-linked to involucrin and probably other cornified envelope proteins by TG1 (Nemes et al. 1991) and possibly TG5 (Candi et al. 2005), forming a monomolecular layer termed the lipid envelope. Eventually these lipids replace the plasma membrane lipid bilayer, which is reabsorbed. Extracellularly, the LB lipids are further metabolized to have a unique composition and are 50% ceramides, 25% cholesterol, and 15% free fatty acids (Feingold 2007). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 Lamellar body Reactome DB_ID: 6814274 ceramide Reactome DB_ID: 6814745 ceramide [ChEBI:17761] ceramide ChEBI CHEBI:17761 Reactome Database ID Release 78 6814745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814745 Reactome R-ALL-6814745 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6814745.2 1 CHOL cholesterol Reactome DB_ID: 176478 cholesterol [ChEBI:16113] cholesterol cholest-5-en-3beta-ol ChEBI CHEBI:16113 Reactome Database ID Release 78 176478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176478 Reactome R-ALL-176478 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-176478.3 COMPOUND C00187 1 fatty acid Reactome DB_ID: 6814303 fatty acid [ChEBI:35366] fatty acid ChEBI CHEBI:35366 Reactome Database ID Release 78 6814303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814303 Reactome R-ALL-6814303 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6814303.2 1 Reactome Database ID Release 78 6814274 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814274 Reactome R-ALL-6814274 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6814274.1 Cornified envelope Reactome DB_ID: 6814278 1 1 Reactome Database ID Release 78 6814278 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814278 Reactome R-HSA-6814278 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814278.2 Reactome Database ID Release 78 6810937 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6810937 Reactome R-HSA-6810937 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6810937.1 3790600 Pubmed 1987 Covalently bound omega-hydroxyacylsphingosine in the stratum corneum Wertz, P W Downing, D T Biochim. Biophys. Acta 917:108-11 12902340 Pubmed 2003 Fusion of lamellar body with plasma membrane is driven by the dual action of annexin II tetramer and arachidonic acid Chattopadhyay, Sandip Sun, Peng Wang, Pengcheng Abonyo, Barack Cross, Nicholas L Liu, L J. Biol. Chem. 278:39675-83 10411887 Pubmed 1999 A novel function for transglutaminase 1: attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation Nemes, Z Marekov, L N Fésüs, L Steinert, P M Proc. Natl. Acad. Sci. U.S.A. 96:8402-7 4045217 Pubmed 1985 Lamellar body-enriched fractions from neonatal mice: preparative techniques and partial characterization Grayson, S Johnson-Winegar, A G Wintroub, B U Isseroff, R R Epstein, E H Elias, P M J. Invest. Dermatol. 85:289-94 24262790 Pubmed 2014 Role of lipids in the formation and maintenance of the cutaneous permeability barrier Feingold, Kenneth R Elias, Peter M Biochim. Biophys. Acta 1841:280-94 9569614 Pubmed 1998 The physical, chemical and functional properties of lipids in the skin and other biological barriers Wertz, P W van den Bergh, B Chem. Phys. Lipids 91:85-96 17872588 Pubmed 2007 Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis Feingold, Kenneth R J. Lipid Res. 48:2531-46 1797938 Pubmed 1991 Structure and function of lamellar bodies, lipid-protein complexes involved in storage and secretion of cellular lipids Schmitz, G Müller, G J. Lipid Res. 32:1539-70 4045218 Pubmed 1985 Lipid composition and acid hydrolase content of lamellar granules of fetal rat epidermis Freinkel, R K Traczyk, T N J. Invest. Dermatol. 85:295-8 LEFT-TO-RIGHT CDSN binds the cornified envelope Corneodesmosomes (CDS) are an ultrastructurally modified form of desmosomes (DS) (Chapman & Walsh 1990). When DS are transformed into CDS between the stratum granulosum and the stratum corneum, the desmoglea loses its trilamellar structure and becomes homogeneously electron dense. On the cytoplasmic side, the attachment plaque (desmosomal plaque) becomes incorporated into the cornified cell envelope (CE). Keratin filaments are connected to the attachment plaque in DS; this association is no longer visible in CDS.<br><br>Like DS, desmoglein and desmocollin constitute the extracellular parts of CDS (Simon et al. 1997), but there is an additional unique extracellular component known as corneodesmosin (CDSN). CDSN is a 52- to 56-kDa glycoprotein produced by keratinocytes that is incorporated into the desmoglea of DS shortly before their transformation into CDS during cornification (Serre et al. 1991). It is stored and secreted by Lamellar bodies. After secretion CDSN localizes to the extracellular structures of CDS and covalently cross-links to the CE. This step coincides with the morphological transformation of DS into CDS. In vitro studies suggest that CDSN mediates homophilic binding to counterparts on adjacent corneocytes (Ishida-Yamamoto & Kishibe 2011). Cleavage of desmoglein, desmocollin and CDSN is a key step in desquamation. Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 CDSN Corneodesmosin CDSN_HUMAN Reactome DB_ID: 6814395 UniProt:Q15517 CDSN CDSN FUNCTION Important for the epidermal barrier integrity.TISSUE SPECIFICITY Exclusively expressed in skin.POLYMORPHISM Genetic variation in CDSN may be associated with susceptibility to psoriasis [MIM:177900] (PubMed:10599883, PubMed:12472658,PubMed:10844560). Various CDSN alleles are known including alleles 1.11, 1.21, 1.31, 1.32, 1.41, 1.42, 1.43, 1.51, 1.52, 2.11, 2.21, 2.22 and 2.23 (PubMed:11169256). UniProt Q15517 33 EQUAL 529 EQUAL Reactome Database ID Release 78 6814395 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814395 Reactome R-HSA-6814395 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814395.1 Cornified envelope:CDSN Reactome DB_ID: 6814723 1 1 Reactome Database ID Release 78 6814723 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814723 Reactome R-HSA-6814723 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814723.1 Reactome Database ID Release 78 6814734 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814734 Reactome R-HSA-6814734 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814734.1 9395522 Pubmed 1997 Characterization and purification of human corneodesmosin, an epidermal basic glycoprotein associated with corneocyte-specific modified desmosomes Simon, M Montézin, M Guerrin, M Durieux, J J Serre, G J. Biol. Chem. 272:31770-6 1748816 Pubmed 1991 Identification of late differentiation antigens of human cornified epithelia, expressed in re-organized desmosomes and bound to cross-linked envelope Serre, G Mils, V Haftek, M Vincent, C Croute, F Réano, A Ouhayoun, J P Bettinger, S Soleilhavoup, J P J. Invest. Dermatol. 97:1061-72 21628128 Pubmed 2011 Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses Jonca, Nathalie Leclerc, Emilie A Caubet, Cécile Simon, Michel Guerrin, Marina Serre, Guy Eur J Dermatol 21:35-42 21424930 Pubmed 2011 Involvement of corneodesmosome degradation and lamellar granule transportation in the desquamation process Ishida-Yamamoto, Akemi Kishibe, Mari Med Mol Morphol 44:1-6 2221982 Pubmed 1990 Desmosomes, corneosomes and desquamation. An ultrastructural study of adult pig epidermis Chapman, S J Walsh, A Arch. Dermatol. Res. 282:304-10 LEFT-TO-RIGHT Late envelope proteins bind cornified envelope:CDSN Late envelope proteins or late cornified envelope proteins (LCEs) are a family of 18 proteins that are expressed after assembly of the cornified envelope (CE) is advanced (Marshall et al. 2000, Kypriotou et al. 2012). They are incorporated into the CE late in the process of envelope maturation during epidermal differentiation. They are probable substrates for epidermal transglutaminases and proposed to link CE proteins and mediate differences in barrier quality, perhaps through interaction with cytoplasmic components of the cornified cell (Marshall et al. 2001). <br><br>Human LCEs fall into distinct structural groups, encoded by genes which form clusters on the genome at 1q21 (Marshall et al. 2001, Niehues et al. 2016). Group 1 are expressed predominantly in epidermis. Group 4 (LEP 13-17) have highest expression in internal epithelia (Wang et al. 2001, Marshall et al. 2001). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 Converted from EntitySet in Reactome LEPs Late envelope proteins Reactome DB_ID: 6814261 LCE1A Late cornified envelope protein 1A LCE1A_HUMAN Reactome DB_ID: 6814305 UniProt:Q5T7P2 LCE1A LCE1A LEP1 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5T7P2 1 EQUAL 110 EQUAL Reactome Database ID Release 78 6814305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814305 Reactome R-HSA-6814305 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814305.1 LCE3D Late cornified envelope protein 3D LCE3D_HUMAN Reactome DB_ID: 6814297 UniProt:Q9BYE3 LCE3D LCE3D LEP16 SPRL6A SPRL6B FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q9BYE3 1 EQUAL 92 EQUAL Reactome Database ID Release 78 6814297 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814297 Reactome R-HSA-6814297 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814297.1 LCE1B Late cornified envelope protein 1B LCE1B_HUMAN Reactome DB_ID: 6814271 UniProt:Q5T7P3 LCE1B LCE1B LEP2 SPRL2A FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5T7P3 1 EQUAL 118 EQUAL Reactome Database ID Release 78 6814271 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814271 Reactome R-HSA-6814271 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814271.1 LCE1C Late cornified envelope protein 1C LCE1C_HUMAN Reactome DB_ID: 6814267 UniProt:Q5T751 LCE1C LCE1C LEP3 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5T751 1 EQUAL 118 EQUAL Reactome Database ID Release 78 6814267 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814267 Reactome R-HSA-6814267 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814267.1 LCE1D Late cornified envelope protein 1D LCE1D_HUMAN Reactome DB_ID: 6814283 UniProt:Q5T752 LCE1D LCE1D LEP4 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5T752 1 EQUAL 114 EQUAL Reactome Database ID Release 78 6814283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814283 Reactome R-HSA-6814283 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814283.1 LCE1E Late cornified envelope protein 1E LCE1E_HUMAN Reactome DB_ID: 6814299 UniProt:Q5T753 LCE1E LCE1E LEP5 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5T753 1 EQUAL 118 EQUAL Reactome Database ID Release 78 6814299 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814299 Reactome R-HSA-6814299 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814299.1 LCE1F Late cornified envelope protein 1F LCE1F_HUMAN Reactome DB_ID: 6814270 UniProt:Q5T754 LCE1F LCE1F LEP6 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta. Expression is observed in the fibroblasts.INDUCTION By UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5T754 1 EQUAL 118 EQUAL Reactome Database ID Release 78 6814270 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814270 Reactome R-HSA-6814270 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814270.1 LCE2A Late cornified envelope protein 2A LCE2A_HUMAN Reactome DB_ID: 6814264 UniProt:Q5TA79 LCE2A LCE2A LEP9 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By calcium and UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5TA79 1 EQUAL 106 EQUAL Reactome Database ID Release 78 6814264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814264 Reactome R-HSA-6814264 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814264.1 LCE2B Late cornified envelope protein 2B LCE2B_HUMAN Reactome DB_ID: 6814295 UniProt:O14633 LCE2B LCE2B LEP10 SPRL1B XP5 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By calcium and UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt O14633 1 EQUAL 110 EQUAL Reactome Database ID Release 78 6814295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814295 Reactome R-HSA-6814295 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814295.1 LCE2C Late cornified envelope protein 2C LCE2C_HUMAN Reactome DB_ID: 6814284 UniProt:Q5TA81 LCE2C LCE2C LEP11 FUNCTION Precursors of the cornified envelope of the stratum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By calcium and UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5TA81 1 EQUAL 110 EQUAL Reactome Database ID Release 78 6814284 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814284 Reactome R-HSA-6814284 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814284.1 LCE2D Late cornified envelope protein 2D LCE2D_HUMAN Reactome DB_ID: 6814300 UniProt:Q5TA82 LCE2D LCE2D LEP12 SPRL1A FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By calcium and UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5TA82 1 EQUAL 110 EQUAL Reactome Database ID Release 78 6814300 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814300 Reactome R-HSA-6814300 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814300.1 LCE3A Late cornified envelope protein 3A LCE3A_HUMAN Reactome DB_ID: 6814296 UniProt:Q5TA76 LCE3A LCE3A LEP13 FUNCTION A structural component of the cornified envelope of the stratum corneum involved in innate cutaneous host defense (Probable). Possesses defensin-like antimicrobial activity against a broad spectrum of Gram-positive and Gram-negative bacteria, both aerobic and anaerobic species. Upon inflammation, may regulate skin barrier repair by shaping cutaneous microbiota composition and immune response to bacterial antigens (PubMed:28634035).TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION Induced upon stimulation with inflammatory cytokines produced by T-helper 1 cells (IL1A, TNF, IFNG) and T-helper 17 cells (IL17A, IL22).SIMILARITY Belongs to the LCE family. UniProt Q5TA76 1 EQUAL 89 EQUAL Reactome Database ID Release 78 6814296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814296 Reactome R-HSA-6814296 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814296.1 LCE3B Late cornified envelope protein 3B LCE3B_HUMAN Reactome DB_ID: 6814269 UniProt:Q5TA77 LCE3B LCE3B LEP14 FUNCTION A structural component of the cornified envelope of the stratum corneum involved in innate cutaneous host defense (Probable). Possesses defensin-like antimicrobial activity against a broad spectrum of Gram-positive and Gram-negative bacteria, both aerobic and anaerobic species. Upon inflammation, may regulate skin barrier repair by shaping cutaneous microbiota composition and immune response to bacterial antigens (PubMed:28634035).TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.SIMILARITY Belongs to the LCE family. UniProt Q5TA77 1 EQUAL 95 EQUAL Reactome Database ID Release 78 6814269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814269 Reactome R-HSA-6814269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814269.1 LCE3C Late cornified envelope protein 3C LCE3C_HUMAN Reactome DB_ID: 6814279 UniProt:Q5T5A8 LCE3C LCE3C LEP15 SPRL3A FUNCTION A structural component of the cornified envelope of the stratum corneum involved in innate cutaneous host defense (Probable). Possesses defensin-like antimicrobial activity against a broad spectrum of Gram-positive and Gram-negative bacteria, both aerobic and anaerobic species. Upon inflammation, may regulate skin barrier repair by shaping cutaneous microbiota composition and immune response to bacterial antigens (PubMed:28634035).TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.SIMILARITY Belongs to the LCE family. UniProt Q5T5A8 1 EQUAL 94 EQUAL Reactome Database ID Release 78 6814279 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814279 Reactome R-HSA-6814279 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814279.1 LCE3E Late cornified envelope protein 3E LCE3E_HUMAN Reactome DB_ID: 6814280 UniProt:Q5T5B0 LCE3E LCE3E LEP17 FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.INDUCTION By UVB.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5T5B0 1 EQUAL 92 EQUAL Reactome Database ID Release 78 6814280 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814280 Reactome R-HSA-6814280 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814280.1 LCE4A Late cornified envelope protein 4A LCE4A_HUMAN Reactome DB_ID: 6814272 UniProt:Q5TA78 LCE4A LCE4A LEP8 SPRL4A FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5TA78 1 EQUAL 99 EQUAL Reactome Database ID Release 78 6814272 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814272 Reactome R-HSA-6814272 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814272.1 LCE5A Late cornified envelope protein 5A LCE5A_HUMAN Reactome DB_ID: 6814260 UniProt:Q5TCM9 LCE5A LCE5A LEP18 SPRL5A FUNCTION Precursors of the cornified envelope of the stratum corneum.TISSUE SPECIFICITY Skin-specific. Expression was readily detected in adult trunk skin, adult arm skin, fetal skin, penal skin, vulva, esophagus and tongue. Not expressed in the cervix, rectum, lung, colon, or placenta. Expression is observed in the heart.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt Q5TCM9 1 EQUAL 118 EQUAL Reactome Database ID Release 78 6814260 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814260 Reactome R-HSA-6814260 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814260.1 LCE6A Late cornified envelope protein 6A LCE6A_HUMAN Reactome DB_ID: 6814262 UniProt:A0A183 LCE6A LCE6A C1orf44 FUNCTION Precursors of the cornified envelope of the stratum corneum.MISCELLANEOUS Belongs to the LCE cluster present on 1q21.SIMILARITY Belongs to the LCE family. UniProt A0A183 1 EQUAL 80 EQUAL Reactome Database ID Release 78 6814262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814262 Reactome R-HSA-6814262 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814262.1 LELP1 Late cornified envelope-like proline-rich protein 1 LELP1_HUMAN Reactome DB_ID: 6814302 UniProt:Q5T871 LELP1 LELP1 SIMILARITY Belongs to the cornifin (SPRR) family. UniProt Q5T871 1 EQUAL 98 EQUAL Reactome Database ID Release 78 6814302 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814302 Reactome R-HSA-6814302 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814302.1 Reactome Database ID Release 78 6814261 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814261 Reactome R-HSA-6814261 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814261.1 Late cornified envelope Reactome DB_ID: 6814275 1 1 Reactome Database ID Release 78 6814275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814275 Reactome R-HSA-6814275 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814275.1 Reactome Database ID Release 78 6814298 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814298 Reactome R-HSA-6814298 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814298.1 10771479 Pubmed 2000 SPRR1 gene induction and barrier formation occur as coordinated moving fronts in terminally differentiating epithelia Marshall, D Hardman, M J Byrne, C J. Invest. Dermatol. 114:967-75 11698679 Pubmed 2001 Differentially expressed late constituents of the epidermal cornified envelope Marshall, D Hardman, M J Nield, K M Byrne, C Proc. Natl. Acad. Sci. U.S.A. 98:13031-6 11350120 Pubmed 2001 Molecular cloning and characterization of a novel mouse epidermal differentiation gene and its promoter Wang, A Johnson, D G MacLeod, M C Genomics 73:284-90 16639001 Pubmed 2006 Expression and regulation of cornified envelope proteins in human corneal epithelium Tong, Louis Corrales, Rosa M Chen, Zhuo Villarreal, Arturo L De Paiva, Cintia S Beuerman, Roger Li, De-Quan Pflugfelder, Stephen C Invest. Ophthalmol. Vis. Sci. 47:1938-46 LEFT-TO-RIGHT 3.4.22.41 3.4.22.40 3.4.22.34 3.4.22.8 3.4.22.28 3.4.22.16 3.4.22.27 3.4.22.38 3.4.22.1 3.4.22.15 3.4.22.14 CASP14 cleaves filaggrin In fully cornified cells, filaggrin is degraded into free amino acids. This high concentration of hydrophillic amino acids is essential for water retention and contributes to the osmolarity, and consequently the flexibility of the cornified layer (Candi et al. 2005). Filaggrin monomers are a direct target for cleavage by the aspartate-specific protease caspase 14 (Denecker et al. 2007, 2008, Hoste et al. 2011, Eckhart & Tschachler 2011). Proteases able to process profilaggrin into fillagrin in vitro include microbial ST14 (Profillagrin endopeptidase 1, PEP1), CAPN1 (mu-calpain), furin, PACE4 and matriptase MT-SP1 (Reising et al. 1995, Yamazaki et al. 1997, Pearton et al. 2001, List et al. 2003, Candi et al. 2005), but these proteases do not appear to have a role in the degradation of filaggrin that occurs at a late stage in keratinization. Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 Mature cornified envelope Reactome DB_ID: 6814763 No FGN-cornified envelope:CDSN Reactome DB_ID: 6814757 1 No FGN-Cornified envelope Reactome DB_ID: 6814758 1 No FGN-late cornified envelope Reactome DB_ID: 6814759 Keratin tonofilament:Desmosome network Reactome DB_ID: 6814760 Reactome Database ID Release 78 6814760 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814760 Reactome R-HSA-6814760 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814760.3 ChEBI 36080 1 1 1 1 1 Reactome Database ID Release 78 6814759 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814759 Reactome R-HSA-6814759 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814759.2 1 Reactome Database ID Release 78 6814758 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814758 Reactome R-HSA-6814758 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814758.3 1 Reactome Database ID Release 78 6814757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814757 Reactome R-HSA-6814757 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814757.2 1 1 Reactome Database ID Release 78 6814763 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814763 Reactome R-HSA-6814763 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814763.1 ACTIVATION GENE ONTOLOGY GO:0004197 Reactome Database ID Release 78 8847672 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847672 Reactome Database ID Release 78 6814387 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814387 Reactome R-HSA-6814387 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814387.1 21654840 Pubmed 2011 Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin Hoste, Esther Kemperman, Patrick Devos, Michael Denecker, Geertrui Kezic, Sanja Yau, Nico Gilbert, Barbara Lippens, Saskia De Groote, Philippe Roelandt, Ria Van Damme, Petra Gevaert, Kris Presland, Richard B Takahara, Hidenari Puppels, Gerwin Caspers, Peter Vandenabeele, P Declercq, Wim J. Invest. Dermatol. 131:2233-41 18250198 Pubmed 2008 Caspase-14 reveals its secrets Denecker, Geertrui Ovaere, Petra Vandenabeele, P Declercq, Wim J. Cell Biol. 180:451-8 LEFT-TO-RIGHT Plasma membrane resorption In differentiating keratinocytes, fusion of lamellar body (LB) membranes with the plasma membrane enriches the plasma membrane with lipids including omega-OH-ceramides. Their fatty acid chains are long enough to span the lipid bilayer, so that the omega-OH projects into the cell. In vitro data have shown that the membrane-anchored transglutaminase 1 enzyme can covalently esterify these ceramides onto glutamine residues of cornified envelope scaffold proteins (Nemes et al. 1999). Eventually, the ceramides replace the bilayer plasma membrane and are thought to serve to interdigitate with and organize the extracellular lipids into characteristic lamellae (Kalinin et al. 2001). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 Mature cornified envelope Reactome DB_ID: 8847742 cornified envelope GENE ONTOLOGY GO:0001533 No FGN-cornified envelope:CDSN Reactome DB_ID: 8847727 CDSN Corneodesmosin CDSN_HUMAN Reactome DB_ID: 8847707 33 EQUAL 529 EQUAL Reactome Database ID Release 78 8847707 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847707 Reactome R-HSA-8847707 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847707.1 1 No FGN-Cornified envelope Reactome DB_ID: 8847716 No FGN-early cornified envelope Reactome DB_ID: 8847722 Keratin tonofilament:Desmosome network Reactome DB_ID: 8847708 Reactome Database ID Release 78 8847708 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847708 Reactome R-HSA-8847708 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847708.3 ChEBI 36080 1 Converted from EntitySet in Reactome Minor CE proteins Reactome DB_ID: 8847726 RPTN Repetin RPTN_HUMAN Reactome DB_ID: 8934838 1 EQUAL 784 EQUAL Reactome Database ID Release 78 8934838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934838 Reactome R-HSA-8934838 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934838.1 TCHH Trichohyalin TRHY_HUMAN Reactome DB_ID: 8934848 1 EQUAL 1943 EQUAL Reactome Database ID Release 78 8934848 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934848 Reactome R-HSA-8934848 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934848.1 CSTA Cystatin-A CYTA_HUMAN Reactome DB_ID: 8934840 1 EQUAL 98 EQUAL Reactome Database ID Release 78 8934840 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934840 Reactome R-HSA-8934840 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934840.1 SKALP PI3(61-117) Peptidase inhibitor 3 Elafin Elastase-specific inhibitor Skin-derived antileukoproteinase WAP four-disulfide core domain protein 14 Protease inhibitor WAP3 Reactome DB_ID: 8934845 61 EQUAL 117 EQUAL Reactome Database ID Release 78 8934845 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934845 Reactome R-HSA-8934845 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934845.1 Reactome Database ID Release 78 8847726 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847726 Reactome R-HSA-8847726 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847726.1 1 Converted from EntitySet in Reactome SPRs Reactome DB_ID: 8934843 SPRR1A Cornifin-A SPR1A_HUMAN Reactome DB_ID: 8934852 1 EQUAL 89 EQUAL Reactome Database ID Release 78 8934852 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934852 Reactome R-HSA-8934852 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934852.1 SPRR1B Cornifin-B SPR1B_HUMAN Reactome DB_ID: 8934847 1 EQUAL 89 EQUAL Reactome Database ID Release 78 8934847 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934847 Reactome R-HSA-8934847 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934847.1 SPRR2A Small proline-rich protein 2A SPR2A_HUMAN Reactome DB_ID: 8934850 1 EQUAL 72 EQUAL Reactome Database ID Release 78 8934850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934850 Reactome R-HSA-8934850 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934850.1 SPRR2B Small proline-rich protein 2B SPR2B_HUMAN Reactome DB_ID: 8934844 1 EQUAL 72 EQUAL Reactome Database ID Release 78 8934844 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934844 Reactome R-HSA-8934844 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934844.1 SPRR2D Small proline-rich protein 2D SPR2D_HUMAN Reactome DB_ID: 8934839 1 EQUAL 72 EQUAL Reactome Database ID Release 78 8934839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934839 Reactome R-HSA-8934839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934839.1 SPRR2E Small proline-rich protein 2E SPR2E_HUMAN Reactome DB_ID: 8934841 1 EQUAL 72 EQUAL Reactome Database ID Release 78 8934841 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934841 Reactome R-HSA-8934841 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934841.1 SPRR2F Small proline-rich protein 2F SPR2F_HUMAN Reactome DB_ID: 8934849 1 EQUAL 72 EQUAL Reactome Database ID Release 78 8934849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934849 Reactome R-HSA-8934849 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934849.1 SPRR2G Small proline-rich protein 2G SPR2G_HUMAN Reactome DB_ID: 8934846 1 EQUAL 73 EQUAL Reactome Database ID Release 78 8934846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934846 Reactome R-HSA-8934846 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934846.1 SPRR3 Small proline-rich protein 3 SPRR3_HUMAN Reactome DB_ID: 8934842 2 EQUAL 169 EQUAL Reactome Database ID Release 78 8934842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934842 Reactome R-HSA-8934842 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934842.1 Reactome Database ID Release 78 8934843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8934843 Reactome R-HSA-8934843 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8934843.1 1 LOR Loricrin LORI_HUMAN Reactome DB_ID: 8847711 1 EQUAL 312 EQUAL Reactome Database ID Release 78 8847711 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847711 Reactome R-HSA-8847711 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847711.1 1 EVPL:PPL:IVL:TGM1 Reactome DB_ID: 8847710 IVL:TGM1 Reactome DB_ID: 8847740 TGM1 Protein-glutamine gamma-glutamyltransferase K ecNumber2.3.2.13/ecNumber TGM1_HUMAN Reactome DB_ID: 8847706 1 EQUAL 817 EQUAL Reactome Database ID Release 78 8847706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847706 Reactome R-HSA-8847706 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847706.1 1 IVL Involucrin INVO_HUMAN Reactome DB_ID: 8847720 1 EQUAL 585 EQUAL Reactome Database ID Release 78 8847720 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847720 Reactome R-HSA-8847720 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847720.1 1 Reactome Database ID Release 78 8847740 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847740 Reactome R-HSA-8847740 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847740.1 1 EVPL:PPL Reactome DB_ID: 8847717 PPL Periplakin PEPL_HUMAN Reactome DB_ID: 8847709 1 EQUAL 1756 EQUAL Reactome Database ID Release 78 8847709 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847709 Reactome R-HSA-8847709 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847709.1 1 EVPL Envoplakin EVPL_HUMAN Reactome DB_ID: 8847741 1 EQUAL 2033 EQUAL Reactome Database ID Release 78 8847741 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847741 Reactome R-HSA-8847741 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847741.1 1 Reactome Database ID Release 78 8847717 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847717 Reactome R-HSA-8847717 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847717.1 1 Reactome Database ID Release 78 8847710 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847710 Reactome R-HSA-8847710 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847710.1 1 Reactome Database ID Release 78 8847722 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847722 Reactome R-HSA-8847722 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847722.2 1 Lamellar body Reactome DB_ID: 8847729 fatty acid Reactome DB_ID: 8847732 Reactome Database ID Release 78 8847732 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847732 Reactome R-ALL-8847732 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8847732.2 1 CHOL cholesterol Reactome DB_ID: 8847704 Reactome Database ID Release 78 8847704 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847704 Reactome R-ALL-8847704 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8847704.3 COMPOUND C00187 1 ceramide Reactome DB_ID: 8847743 Reactome Database ID Release 78 8847743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847743 Reactome R-ALL-8847743 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8847743.2 1 Reactome Database ID Release 78 8847729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847729 Reactome R-ALL-8847729 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8847729.1 1 Reactome Database ID Release 78 8847716 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847716 Reactome R-HSA-8847716 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847716.3 1 Reactome Database ID Release 78 8847727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847727 Reactome R-HSA-8847727 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847727.2 1 1 Reactome Database ID Release 78 8847742 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847742 Reactome R-HSA-8847742 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847742.1 Reactome Database ID Release 78 6814764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814764 Reactome R-HSA-6814764 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814764.1 11590230 Pubmed 2001 Assembly of the epidermal cornified cell envelope Kalinin, A Marekov, L N Steinert, P M J. Cell. Sci. 114:3069-70 LEFT-TO-RIGHT PERP binds desmosomes PERP (p53 effector related to PMP-22) is a p53/p63 target gene involved in DNA damage-induced apoptosis (Flores et al. 2002). It is a tetraspan membrane protein,distantly related to members of the claudin/PMP-22/EMP family of four-pass membrane proteins (Attardi et al. 2000). It has an epithelial-specific expression pattern during embryogenesis and localizes to desmosomes. Perp -/- knockout mice exhibit numerous desmosomal structural defects, suggesting a role for Perp in promoting the stable assembly of desmosomal adhesive complexes (Ihrie et al. 2005). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 PERP p53 apoptosis effector related to PMP-22 Reactome DB_ID: 6800837 UniProt:Q96FX8 PERP PERP KCP1 KRTCAP1 PIGPC1 THW FUNCTION Component of intercellular desmosome junctions. Plays a role in stratified epithelial integrity and cell-cell adhesion by promoting desmosome assembly. Plays a role as an effector in the TP53-dependent apoptotic pathway (By similarity).TISSUE SPECIFICITY Expressed in skin, heart, placental, liver, pancreas, keratinocytes and dermal fibroblasts.SIMILARITY Belongs to the TMEM47 family. UniProt Q96FX8 1 EQUAL 193 EQUAL Reactome Database ID Release 78 6800837 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800837 Reactome R-HSA-6800837 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800837.1 Desmosome:PERP Reactome DB_ID: 8848046 1 1 Reactome Database ID Release 78 8848046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8848046 Reactome R-HSA-8848046 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8848046.2 Reactome Database ID Release 78 6814695 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814695 Reactome R-HSA-6814695 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814695.1 15797384 Pubmed 2005 Perp is a p63-regulated gene essential for epithelial integrity Ihrie, Rebecca A Marques, Michelle R Nguyen, Bichchau T Horner, Jennifer S Papazoglu, Cristian Bronson, Roderick T Mills, Alea A Attardi, Laura D Cell 120:843-56 11932750 Pubmed 2002 p63 and p73 are required for p53-dependent apoptosis in response to DNA damage Flores, Elsa R Tsai, Kenneth Y Crowley, Denise Sengupta, Shomit Yang, Annie McKeon, Frank Jacks, Tyler Nature 416:560-4 10733530 Pubmed 2000 PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family Attardi, L D Reczek, E E Cosmas, C Demicco, E G McCurrach, M E Lowe, S W Jacks, T Genes Dev. 14:704-18 LEFT-TO-RIGHT Kazrin binds periplakin Kazrin (KAZN) is an evolutionarily-conserved cytoplasmic and nuclear protein that was identified as a binding partner of periplakin (PPL), a component of epidermal desmosomes (DS) and the cornified envelope (CE) (Groot et al. 2004). <br><br>Kazrin has at least 5 different isoforms. Overexpression of the short isoform kazrinE stimulates the terminal differentiation of cultured human keratinocytes and is associated with a reduction in F-actin content, disruption of DS assembly, and changes in cell shape. Overexpression of activated RhoA rescues the effects on cell shape and adhesion. Conversely, knockdown of the longest isoform kazrinA impairs terminal differentiation, independently of RhoA activity (Sevilla et al. 2008a). KazrinE colocalizes with stabilized microtubules in differentiating keratinocytes (Nachat et al. 2009). All KAZN isoforms can form complexes with one another (Nachat et al. 2009), suggesting that like periplakin and envoplakin, it may form part of the cortical scaffold that integrates the actin cytoskeleton with DS (Ruhrberg et al. 1997, Kalinin et al. 2001, Groot et al. 2004). In Xenopus embryos, depletion of endogenous KAZN results in striking defects in axial elongation, muscle and notochord differentiation, and epidermal morphogenesis. These effects are believed to be due to disruption of cell-cell junctions (Sevilla et al. 2008b, Cho et al. 2010). However, mice with a knockout that removes exons 5-15 of KAZN had normal epidermal morphogenesis and homeostasis (Chhatriwala et al. 2012). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 KAZN Kazrin KAZRN_HUMAN Reactome DB_ID: 6814378 UniProt:Q674X7 KAZN KAZN C1orf196 KAZ KIAA1026 HRIHFB2003 FUNCTION Component of the cornified envelope of keratinocytes. May be involved in the interplay between adherens junctions and desmosomes. The function in the nucleus is not known.SUBUNIT Isoform 2, isoform 3 and isoform 4 interact with PPL N-terminus.TISSUE SPECIFICITY Isoform 2, isoform 3 and isoform 4 are expressed in several cell lines including keratinocytes and bladder and epidermoid carcinoma (at protein level). Isoform 2, isoform 3 and isoform 4 are expressed in hair follicle and interfollicular epidermis (at protein level).SIMILARITY Belongs to the kazrin family. UniProt Q674X7 1 EQUAL 775 EQUAL Reactome Database ID Release 78 6814378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814378 Reactome R-HSA-6814378 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814378.1 KAZN:PPL Reactome DB_ID: 6814328 1 1 Reactome Database ID Release 78 6814328 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814328 Reactome R-HSA-6814328 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814328.1 Reactome Database ID Release 78 6814374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6814374 Reactome R-HSA-6814374 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6814374.1 21062899 Pubmed 2010 Xenopus Kazrin interacts with ARVCF-catenin, spectrin and p190B RhoGAP, and modulates RhoA activity and epithelial integrity Cho, Kyucheol Vaught, Travis G Ji, Hong Gu, Dongmin Papasakelariou-Yared, Catherine Horstmann, Nicola Jennings, Jean Marie Lee, Moonsup Sevilla, Lisa M Kloc, Malgorzata Reynolds, Albert B Watt, Fiona M Brennan, Richard G Kowalczyk, Andrew P McCrea, Pierre D J. Cell. Sci. 123:4128-44 22513779 Pubmed 2012 Exons 5-15 of kazrin are dispensable for murine epidermal morphogenesis and homeostasis Chhatriwala, Mariya K Cipolat, Sara Sevilla, Lisa M Nachat, Rachida Watt, Fiona M J. Invest. Dermatol. 132:1977-87 18840647 Pubmed 2008 Kazrin regulates keratinocyte cytoskeletal networks, intercellular junctions and differentiation Sevilla, Lisa M Nachat, Rachida Groot, Karen R Watt, Fiona M J. Cell. Sci. 121:3561-9 19843585 Pubmed 2009 KazrinE is a desmosome-associated liprin that colocalises with acetylated microtubules Nachat, Rachida Cipolat, Sara Sevilla, Lisa M Chhatriwala, Mariya Groot, Karen R Watt, Fiona M J. Cell. Sci. 122:4035-41 18498100 Pubmed 2008 KazrinA is required for axial elongation and epidermal integrity in Xenopus tropicalis Sevilla, Lisa M Rana, Amer A Watt, Fiona M Smith, James C Dev. Dyn. 237:1718-25 LEFT-TO-RIGHT 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 ST14 hydrolyzes and activates KLK5 ST14 (Suppressor of tumorigenicity 14, also known as matriptase) associated with the plasma membrane catalyzes the hydrolytic cleavage of proKLK5 (pro-Kallekrein-5) to yield active KLK5 enzyme. The activity of human ST14 enzyme is inferred from that of its well-characterized mouse homolog (Sales et al. 2010). Consistent with this inference, deficiencies of the human enzyme are associated with an ichthyosis syndrome (MIM 602400) as is a knockout mutation of mouse St14 (Alef et al. 2009). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 H2O water Reactome DB_ID: 109276 extracellular region GENE ONTOLOGY GO:0005576 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 109276 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109276 Reactome R-ALL-109276 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-109276.4 COMPOUND C00001 proKLK5 KLK5(23-293) proKallikrein-5 proSCTE pro-Stratum corneum tryptic enzyme Reactome DB_ID: 8849836 23 EQUAL 293 EQUAL Reactome Database ID Release 78 8849836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849836 Reactome R-HSA-8849836 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849836.1 KLK5 KLK5(67-293) Kallikrein-5 SCTE Stratum corneum tryptic enzyme Reactome DB_ID: 8849629 67 EQUAL 293 EQUAL Reactome Database ID Release 78 8849629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849629 Reactome R-HSA-8849629 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849629.1 KLK5(23-66) KLK5 propeptide Kallikrein-5 propeptide SCTE propeptide Stratum corneum tryptic enzyme propeptide Reactome DB_ID: 8849839 23 EQUAL 66 EQUAL Reactome Database ID Release 78 8849839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849839 Reactome R-HSA-8849839 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849839.1 ACTIVATION GENE ONTOLOGY GO:0004252 Reactome Database ID Release 78 8849854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849854 Reactome Database ID Release 78 8849826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849826 Reactome R-HSA-8849826 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849826.1 20657595 Pubmed 2010 Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome Sales, Katiuchia Uzzun Masedunskas, Andrius Bey, Alexandra L Rasmussen, Amber L Weigert, Roberto List, Karin Szabo, Roman Overbeek, Paul A Bugge, Thomas H Nat. Genet. 42:676-83 18843291 Pubmed 2009 Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing Alef, Thomas Torres, Serena Hausser, Ingrid Metze, Dieter Türsen, Umit Lestringant, Gilles G Hennies, Hans Christian J. Invest. Dermatol. 129:862-9 LEFT-TO-RIGHT SPINK5(490-624) binds KLK5 The D8D9 fragment of SPINK5 (Serine protease inhibitor Kazal-type 5, also known as LEKTI, Lympho-epithelial Kazal-type-related inhibitor), consisting of residues 490 - 624 of the full-length protein, binds to KLK5 (Kallikrein-5), inactivating the latter. At neutral pH, complex formation is effectively irreversible. In normal skin, this event occurs extracellularly in the stratum corneum of the skin. As the complex is carried into layers nearer the surface of the skin, falling pH triggers its dissociation and release of active KLK5. Mutations that inactivate SPINK5 are associated with a severe skin disorder, Netherton syndrome (NS, MIM 256500), whose symptoms include premature desquamation (Deraison et al, 2007; Fortugno et al. 2011). Consistent with the hypothesis that SPINK5-mediated inhibition of KLK5 activity is a key feature of regulating normal desquamation, the NS-like phenotype of mice whose SPINK5-homologous gene has been knocked out is reversed in mice missing both SPINK5 and KLK5 activitiies (Furio et al. 2015). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 LEKTI D8-D9 SPINK5(490-624) Serine protease inhibitor Kazal-type 5, D8-D9 Reactome DB_ID: 8849665 UniProt:Q9NQ38 SPINK5 SPINK5 FUNCTION Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating and desquamation-involved proteases. Inhibits KLK5, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin.TISSUE SPECIFICITY Highly expressed in the thymus and stratum corneum. Also found in the oral mucosa, parathyroid gland, Bartholin's glands, tonsils, and vaginal epithelium. Very low levels are detected in lung, kidney, and prostate.DOMAIN Contains at least one active inhibitory domain for trypsin (domain 6).PTM Proteolytically processed by furin in individual domains (D1, D5, D6, D8 through D11, and D9 through D15) exhibiting various inhibitory potentials for multiple proteases. UniProt Q9NQ38 490 EQUAL 624 EQUAL Reactome Database ID Release 78 8849665 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849665 Reactome R-HSA-8849665 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849665.1 KLK5:LEKTI KLK5:SPINK5 Reactome DB_ID: 8849656 1 1 Reactome Database ID Release 78 8849656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849656 Reactome R-HSA-8849656 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849656.1 Reactome Database ID Release 78 8849646 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849646 Reactome R-HSA-8849646 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849646.1 17596512 Pubmed 2007 LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction Deraison, Celine Bonnart, Chrystelle Lopez, Frederic Besson, Celine Robinson, Ross Jayakumar, A Wagberg, Fredrik Brattsand, Maria Hachem, Jean Pierre Leonardsson, Goran Hovnanian, Alain Mol. Biol. Cell 18:3607-19 26390218 Pubmed 2015 KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome Furio, Laetitia Pampalakis, Georgios Michael, Iacovos P Nagy, Andras Sotiropoulou, Georgia Hovnanian, Alain PLoS Genet. 11:e1005389 LEFT-TO-RIGHT Dissociation of the SPINK5:KLK5 complex at low pH At low pH, the complex of the D8D9 fragment of SPINK5 (Serine protease inhibitor Kazal-type 5, also known as LEKTI, Lympho-epithelial Kazal-type-related inhibitor), consisting of residues 490 - 624 of the full-length protein, and KLK5 (Kallikrein-5) dissociates, releasing active KLK5 protease. In normal skin, this event occurs extracellularly in upper layers of the skin (Deraison et al. 2007). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 Reactome Database ID Release 78 8849638 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849638 Reactome R-HSA-8849638 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849638.3 ACTIVATION Reactome Database ID Release 78 8849621 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849621 Reactome R-HSA-8849621 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849621.1 H+ hydron Reactome DB_ID: 351626 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 78 351626 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351626 Reactome R-ALL-351626 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-351626.4 COMPOUND C00080 LEFT-TO-RIGHT 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 KLK5 cleaves and activates CELA2 In the low-pH environment of the upper layers of the stratum corneum, KLK5 (Kallikrein 5) dissociates from its complex with SPINK5 (Serine protease inhibitor kazal-type 5) (Deraison et al. 2007) and is free to cleave proCELA2 (Elastase 2), activating it (Bonnart et al. 2010). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 proELA2A proCELA2A pro-Chymotrypsin-like elastase family member 2A pro-Elastase 2A Reactome DB_ID: 8849859 16 EQUAL 269 EQUAL Reactome Database ID Release 78 8849859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849859 Reactome R-HSA-8849859 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849859.1 ELA2A propeptide CELA2A propeptide Chymotrypsin-like elastase family member 2A propeptide Elastase 2A propeptide Reactome DB_ID: 8849856 16 EQUAL 28 EQUAL Reactome Database ID Release 78 8849856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849856 Reactome R-HSA-8849856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849856.1 ELA2A CELA2A Chymotrypsin-like elastase family member 2A Elastase 2A Reactome DB_ID: 8849616 29 EQUAL 269 EQUAL Reactome Database ID Release 78 8849616 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849616 Reactome R-HSA-8849616 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849616.1 ACTIVATION Reactome Database ID Release 78 8849630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849630 Reactome Database ID Release 78 8849857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849857 Reactome R-HSA-8849857 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849857.2 LEFT-TO-RIGHT 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 KLK5 cleaves and activates KLK8 In vitro, KLK5 (Kallikrein 5) catalyzes the slow cleavage of a four-residue aminoterminal propeptide from proKLK8 (pro-Kallekrein 8), to generate active KLK8. The abundance of KLK8 in the stratum corneum and its serine endopeptidase activity are consistent with a role for KLK8 in formation of the stratum corneum, desquamation, or both. Physiological substrates for KLK8 remains to be identified, however, as do possible additional activators of it (Eissa et al. 2011). A possible pathogenic role for KLK8 is suggested by the recent demonstration that it can mediate the extracellular cleavage of the L1 capsid protein of human papilloma viruses, facilitating their infection of human host cells (Cerqueira et al. 2015). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 proKLK8 pro-Kallikrein-8 Reactome DB_ID: 8850832 UniProt:O60259 KLK8 KLK8 NRPN PRSS19 TADG14 UNQ283/PRO322 FUNCTION Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.ACTIVITY REGULATION Inhibited by a range of serine protease inhibitors including antipain, aprotinin, leupeptin, benzamidine and soybean trypsin inhibitor.SUBUNIT Interacts with SPINK9.TISSUE SPECIFICITY Isoform 1 is predominantly expressed in the pancreas. Isoform 2 is expressed in adult brain and hippocampus. Isoform 1 and isoform 2 are found in fetal brain and placenta. Detected in salivary gland, uterus, thymus, breast, testis and kidney but not in spleen, liver, lung or normal ovarian tissue. Displays an 11.5-fold increase in Alzheimer disease hippocampus compared to controls and is overexpressed in some ovarian carcinomas. Expressed at low levels in normal skin while high levels are found in psoriasis vulgaris, seborrheic keratosis, lichen planus and squamous cell carcinoma skin samples. Expressed in the keratinocytes.MISCELLANEOUS Expressed at high levels in serum, ascites fluid and tumor cytosol of advanced stage ovarian cancer patients and may serve as a marker of ovarian cancer.SIMILARITY Belongs to the peptidase S1 family. Kallikrein subfamily. UniProt O60259 29 EQUAL 260 EQUAL Reactome Database ID Release 78 8850832 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850832 Reactome R-HSA-8850832 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850832.1 KLK8 propeptide Kallikrein-8 propeptide Reactome DB_ID: 8850829 29 EQUAL 32 EQUAL Reactome Database ID Release 78 8850829 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850829 Reactome R-HSA-8850829 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850829.1 KLK8 Kallikrein-8 neuropsin Reactome DB_ID: 8850833 33 EQUAL 260 EQUAL Reactome Database ID Release 78 8850833 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850833 Reactome R-HSA-8850833 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850833.1 ACTIVATION Reactome Database ID Release 78 8850831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850831 Reactome R-HSA-8850831 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850831.2 25926655 Pubmed 2015 Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells Cerqueira, Carla Samperio Ventayol, Pilar Vogeley, Christian Schelhaas, Mario J. Virol. 89:7038-52 20940292 Pubmed 2011 Kallikrein-related peptidase-8 (KLK8) is an active serine protease in human epidermis and sweat and is involved in a skin barrier proteolytic cascade Eissa, Azza Amodeo, Vanessa Smith, Chistopher R Diamandis, Eleftherios P J. Biol. Chem. 286:687-706 LEFT-TO-RIGHT SPINK6 binds KLK12 Extracellular SPINK6 (Serine protease inhibitor Kazal-type 6) binds KLK12 (kallekrein-related peptidase 12), inactivating the latter (Kantyka et al. 2011). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 KLK12 Kallikrein-12 Reactome DB_ID: 8850802 UniProt:Q9UKR0 KLK12 KLK12 KLKL5 UNQ669/PRO1303 SIMILARITY Belongs to the peptidase S1 family. Kallikrein subfamily. UniProt Q9UKR0 22 EQUAL 248 EQUAL Reactome Database ID Release 78 8850802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850802 Reactome R-HSA-8850802 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850802.1 SPINK6 Serine protease inhibitor Kazal-type 6 Reactome DB_ID: 8850798 UniProt:Q6UWN8 SPINK6 SPINK6 UNQ844/PRO1782 FUNCTION Serine protease inhibitor selective for kallikreins. Efficiently inhibits KLK4, KLK5, KLK6, KLK7, KLK12, KLK13 and KLK14. Doesn't inhibit KLK8. UniProt Q6UWN8 24 EQUAL 80 EQUAL Reactome Database ID Release 78 8850798 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850798 Reactome R-HSA-8850798 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850798.1 KLK12:SPINK6 Reactome DB_ID: 8850791 1 1 Reactome Database ID Release 78 8850791 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850791 Reactome R-HSA-8850791 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850791.1 Reactome Database ID Release 78 8850786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850786 Reactome R-HSA-8850786 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850786.1 21439340 Pubmed 2011 Inhibition of kallikrein-related peptidases by the serine protease inhibitor of Kazal-type 6 Kantyka, Tomasz Fischer, Jan Wu, Zhihong Declercq, Wim Reiss, Karina Schröder, Jens-Michael Meyer-Hoffert, Ulf Peptides 32:1187-92 LEFT-TO-RIGHT SPINK6 binds KLK13 Extracellular SPINK6 (Serine protease inhibitor Kazal-type 6) binds KLK13 (kallekrein-related peptidase 13), inactivating the latter (Kantyka et al. 2011). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 KLK13 Kallikrein-13 ecNumber3.4.21.-/ecNumber KLK13_HUMAN Reactome DB_ID: 2990873 UniProt:Q9UKR3 KLK13 KLK13 KLKL4 TISSUE SPECIFICITY Expressed in prostate, breast, testis and salivary gland.SIMILARITY Belongs to the peptidase S1 family. Kallikrein subfamily. UniProt Q9UKR3 26 EQUAL 277 EQUAL Reactome Database ID Release 78 2990873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2990873 Reactome R-HSA-2990873 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2990873.2 KLK13:SPINK6 Reactome DB_ID: 8850785 1 1 Reactome Database ID Release 78 8850785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850785 Reactome R-HSA-8850785 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850785.1 Reactome Database ID Release 78 8850797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850797 Reactome R-HSA-8850797 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850797.1 LEFT-TO-RIGHT SPINK6 binds KLK14 Extracellular SPINK6 (Serine protease inhibitor Kazal-type 6) binds KLK14 (kallekrein-related peptidase 14), inactivating the latter. KLK14 activity contributes to the process of desquamation, and SPINK6 binding may play a role in the regulation of that process (Meyer-Hoffert et al. 2010). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 KLK14 Kallikrein-14 KLK14_HUMAN Reactome DB_ID: 5694595 UniProt:Q9P0G3 KLK14 KLK14 KLKL6 FUNCTION Serine-type endopeptidase with a dual trypsin-like and chymotrypsin-like substrate specificity. May activate/inactivate the proteinase-activated receptors F2R, F2RL1 and F2RL3 and other kallikreins including KLK1, KLK3, KLK5 and KLK11. May function in seminal clot liquefaction through direct cleavage of the semenogelin SEMG1 and SEMG2 and activation of KLK3. May function through desmoglein DSG1 cleavage in epidermal desquamation a process by which the most superficial corneocytes are shed from the skin surface. May be involved in several aspects of tumor progression including growth, invasion and angiogenesis.ACTIVITY REGULATION Inhibited by SERPINA1, SERPINC1, SERPINE1, SERPINF2, aprotinin, soybean, trypsin inhibitor and leupeptin. Inhibited by serine protease inhibitor SPINK5. Has an autoproteolytic activity which may have a regulatory effect. Activated by citrate and inhibited by zinc and to a lower extent by manganese.TISSUE SPECIFICITY Highly expressed in CNS, bone marrow and fetal liver. Also expressed in breast, thyroid, kidney, colon, pancreas, spleen, prostate, uterus, small intestine, placenta and skeletal muscle. Among 40 tissues tested, the highest expression is detected in skin followed by breast and prostate (at protein level). Expressed in stratum corneum by sweat ducts and sweat glands and detected in sweat (at protein level).INDUCTION Up-regulated by steroid hormone.PTM Proteolytic cleavage of the activation peptide produces the active enzyme.SIMILARITY Belongs to the peptidase S1 family. Kallikrein subfamily.CAUTION It is uncertain whether Met-1 or Met-17 is the initiator. UniProt Q9P0G3 41 EQUAL 267 EQUAL Reactome Database ID Release 78 5694595 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5694595 Reactome R-HSA-5694595 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5694595.1 KLK14:SPINK6 Reactome DB_ID: 8850790 1 1 Reactome Database ID Release 78 8850790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850790 Reactome R-HSA-8850790 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850790.1 Reactome Database ID Release 78 8850777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850777 Reactome R-HSA-8850777 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850777.1 20667819 Pubmed 2010 Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases Meyer-Hoffert, Ulf Wu, Zhihong Kantyka, Tomasz Fischer, Jan Latendorf, Ties Hansmann, Britta Bartels, Joachim He, Yinghong Gläser, Regine Schröder, Jens-Michael J. Biol. Chem. 285:32174-81 LEFT-TO-RIGHT SPINK6 binds KLK5 Extracellular SPINK6 (Serine protease inhibitor Kazal-type 6) binds KLK5 (kallekrein-related peptidase 5), inactivating the latter. KLK5 activity contributes to the process of desquamation, and SPINK6 binding may play a role in the regulation of that process (Meyer-Hoffert et al. 2010). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 KLK5:SPINK6 Reactome DB_ID: 8850796 1 1 Reactome Database ID Release 78 8850796 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850796 Reactome R-HSA-8850796 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850796.1 Reactome Database ID Release 78 8850794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850794 Reactome R-HSA-8850794 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850794.1 LEFT-TO-RIGHT SPINK9 binds KLK5 Extracellular SPINK9 (Serine protease inhibitor Kazal-type 6) binds KLK5 (kallekrein-related peptidase 5), inactivating the latter. KLK5 activity contributes to the process of desquamation, and SPINK9 binding may play a role in the regulation of that process (Brattsand et al. 2009; Meyer-Hoffert et al. 2009). Authored: Jupe, Steve, 2016-03-10 Reviewed: Blumenberg, Miroslav, 2016-08-12 Edited: Jupe, Steve, 2016-08-09 SPINK9 Serine protease inhibitor Kazal-type 9 LEKTI-2 Lymphoepithelial Kazal-type-related inhibitor 2 Reactome DB_ID: 8850814 UniProt:Q5DT21 SPINK9 SPINK9 LEKTI2 FUNCTION Serine protease inhibitor which specifically inhibits KLK5. May contribute to the regulation of the desquamation process in skin by inhibiting KLK5.SUBUNIT Dimer. Interacts with KLK5 and KLK8.TISSUE SPECIFICITY Skin. Highly expressed at sites of hyperkeratosis. Also detected in thymus, tonsils, testis, pancreas, liver, placenta and brain. Expressed at stratum granulosum and stratum corneum at palmar and plantar sites (at protein level). UniProt Q5DT21 26 EQUAL 86 EQUAL Reactome Database ID Release 78 8850814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850814 Reactome R-HSA-8850814 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850814.1 KLK5:SPINK9 Reactome DB_ID: 8850817 1 1 Reactome Database ID Release 78 8850817 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850817 Reactome R-HSA-8850817 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850817.1 Reactome Database ID Release 78 8850818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8850818 Reactome R-HSA-8850818 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8850818.1 19194479 Pubmed 2009 SPINK9: a selective, skin-specific Kazal-type serine protease inhibitor Brattsand, Maria Stefansson, Kristina Hubiche, Thomas Nilsson, Stefan K Egelrud, Torbjorn J. Invest. Dermatol. 129:1656-65 19190773 Pubmed 2009 Identification of lympho-epithelial Kazal-type inhibitor 2 in human skin as a kallikrein-related peptidase 5-specific protease inhibitor Meyer-Hoffert, Ulf Wu, Zhihong Schröder, Jens-Michael PLoS ONE 4:e4372 LEFT-TO-RIGHT 3.1.1.34 LIPs hydrolyse TG to DAG and RCOOH Lipases are enzymes that hydrolyse dietary lipids such as fats, oils and triglycerides. The majority of human lipases are secreted by the pancreas and function mainly in the digestive system. Lipase members K, M and N (LIPK, M and N), however, all appear to play a role in the last step of keratinocyte differentiation where they are proposed to hydrolyse triglycerides to free fatty acids and glycerol which is essential to stratum corneum hydration (Toulza et al. 2007). Authored: Jassal, Bijay, 2015-07-30 Reviewed: D'Eustachio, Peter, 2015-09-14 Edited: Jupe, Steve, 2017-03-21 TAGs triacylglycerols triglyceride Reactome DB_ID: 171126 triglyceride [ChEBI:17855] triglyceride ChEBI CHEBI:17855 Reactome Database ID Release 78 171126 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=171126 Reactome R-ALL-171126 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-171126.3 RCOOH carboxylate carboxylic acid Reactome DB_ID: 6789319 carboxylic acid [ChEBI:33575] carboxylic acid RC(=O)OH acidos carboxilicos Karbonsaeure Carbonsaeuren acides carboxyliques Carbonsaeure acide carboxylique acido carboxilico ChEBI CHEBI:33575 Reactome Database ID Release 78 6789319 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789319 Reactome R-ALL-6789319 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6789319.3 DAG DAGs diacylglycerols diglyceride diglycerides Reactome DB_ID: 174675 diglyceride [ChEBI:18035] diglyceride ChEBI CHEBI:18035 Reactome Database ID Release 78 174675 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174675 Reactome R-ALL-174675 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-174675.4 ACTIVATION Converted from EntitySet in Reactome lipases keratinocyte LIPs LIPG,J,K,M,N Reactome DB_ID: 6789317 LIPK Lipase member K ecNumber3.1.1.-/ecNumber LIPK_HUMAN Reactome DB_ID: 6789300 UniProt:Q5VXJ0 LIPK LIPK LIPL2 FUNCTION Plays a highly specific role in the last step of keratinocyte differentiation. May have an essential function in lipid metabolism of the most differentiated epidermal layers.TISSUE SPECIFICITY Exclusively expressed in the epidermis within the granular keratinocytes.SIMILARITY Belongs to the AB hydrolase superfamily. Lipase family. UniProt Q5VXJ0 20 EQUAL 399 EQUAL Reactome Database ID Release 78 6789300 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789300 Reactome R-HSA-6789300 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6789300.1 LIPM Lipase member M ecNumber3.1.1.-/ecNumber LIPM_HUMAN Reactome DB_ID: 6789306 UniProt:Q5VYY2 LIPM LIPM LIPL3 FUNCTION Plays a highly specific role in the last step of keratinocyte differentiation. May have an essential function in lipid metabolism of the most differentiated epidermal layers.TISSUE SPECIFICITY Exclusively expressed in the epidermis within the granular keratinocytes.SIMILARITY Belongs to the AB hydrolase superfamily. Lipase family. UniProt Q5VYY2 34 EQUAL 423 EQUAL Reactome Database ID Release 78 6789306 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789306 Reactome R-HSA-6789306 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6789306.1 LIPN Lipase member N ecNumber3.1.1.-/ecNumber LIPN_HUMAN Reactome DB_ID: 6789321 UniProt:Q5VXI9 LIPN LIPN LIPL4 FUNCTION Plays a highly specific role in the last step of keratinocyte differentiation. May have an essential function in lipid metabolism of the most differentiated epidermal layers.TISSUE SPECIFICITY Highly expressed in the epidermis in the granular keratinocytes. Also detected in other tissues, although at much lower levels, including lung and spleen.DEVELOPMENTAL STAGE Up-regulated during epidermal differentiation.SIMILARITY Belongs to the AB hydrolase superfamily. Lipase family. UniProt Q5VXI9 19 EQUAL 398 EQUAL Reactome Database ID Release 78 6789321 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789321 Reactome R-HSA-6789321 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6789321.1 LIPJ Lipase member J ecNumber3.1.1.-/ecNumber LIPJ_HUMAN Reactome DB_ID: 6789309 UniProt:Q5W064 LIPJ LIPJ LIPL1 SIMILARITY Belongs to the AB hydrolase superfamily. Lipase family. UniProt Q5W064 1 EQUAL 366 EQUAL Reactome Database ID Release 78 6789309 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789309 Reactome R-HSA-6789309 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6789309.1 Reactome Database ID Release 78 6789317 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789317 Reactome R-HSA-6789317 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6789317.1 GENE ONTOLOGY GO:0004465 Reactome Database ID Release 78 6789311 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789311 Reactome Database ID Release 78 6789310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6789310 Reactome R-HSA-6789310 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6789310.1 17562024 Pubmed 2007 Large-scale identification of human genes implicated in epidermal barrier function Toulza, Eve Mattiuzzo, Nicolas R Galliano, Marie-Florence Jonca, Nathalie Dossat, Carole Jacob, Daniel de Daruvar, Antoine Wincker, Patrick Serre, Guy Guerrin, Marina Genome Biol. 8:R107 Reactome Database ID Release 78 6809371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6809371 Reactome R-HSA-6809371 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6809371.3 12613658 Pubmed 2003 Keratins: a structural scaffold with emerging functions Kirfel, J Magin, T M Reichelt, J Cell. Mol. Life Sci. 60:56-71 21545505 Pubmed 2011 Order and disorder in corneocyte adhesion Ishida-Yamamoto, Akemi Igawa, Satomi Kishibe, Mari J. Dermatol. 38:645-54 15737187 Pubmed 2005 Transglutaminase function in epidermis Eckert, Richard L Sturniolo, Michael T Broome, Ann-Marie Ruse, Monica Rorke, Ellen A J. Invest. Dermatol. 124:481-92 25514792 Pubmed 2014 Calcium--a central regulator of keratinocyte differentiation in health and disease Elsholz, Floriana Harteneck, Christian Muller, Walter Friedland, Kristina Eur J Dermatol 24:650-61 23792051 Pubmed 2013 Cell death by cornification Eckhart, Leopold Lippens, Saskia Tschachler, Erwin Declercq, Wim Biochim. Biophys. Acta 1833:3471-80 11121154 Pubmed 2000 Terminal differentiation of human keratinocytes and stratum corneum formation is associated with caspase-14 activation Eckhart, L Declercq, W Ban, J Rendl, M Lengauer, B Mayer, C Lippens, S Vandenabeele, P Tschachler, E J. Invest. Dermatol. 115:1148-51 8601731 Pubmed 1996 Sequence and expression patterns of mouse SPR1: Correlation of expression with epithelial function Kartasova, T Darwiche, N Kohno, Y Koizumi, H Osada, S Huh, N Lichti, U Steinert, P M Kuroki, T J. Invest. Dermatol. 106:294-304 GENE ONTOLOGY GO:0070268 gene ontology term for cellular process MI MI:0359