BioPAX pathway converted from "Expression of IL4, IL13-upregulated extracellular proteins" in the Reactome database.LEFT-TO-RIGHTExpression of IL4, IL13-upregulated extracellular proteinsIn human peripheral blood monocytes IL4 and IL13 significantly upregulate the levels of several extracellular proteins involved in inflammatory resolution including fibronectin (FN1), coagulation factor XIII (FXIII), annexin 1 (ANXA1), collagen type 1 alpha 2 (COL1A2), laminin alpha-5 (LAMA5) and C-C motif chemokine 22 (CCL22) (Chaitidis et al. 2005, Jinnin et al. 2004, Yakubenko et al. 2011).Authored: Jupe, Steve, 2015-07-01Reviewed: Leibovich, Samuel, 2016-09-02Edited: Jupe, Steve, 2016-09-02Converted from EntitySet in ReactomeIL4,IL13-upregulated extracellular genesReactome DB_ID: 6789505FN1 geneReactome DB_ID: 6789503nucleoplasmGENE ONTOLOGYGO:0005654ENSEMBL:ENSG00000115414 FN1FN1FNHomo sapiensNCBI Taxonomy9606ENSEMBLENSG00000115414Reactome Database ID Release 716789503Database 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=6789503ReactomeR-HSA-67895031Reactome 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-6789503.1Reactomehttp://www.reactome.orgF13A1 geneReactome DB_ID: 6789518ENSEMBL:ENSG00000124491 F13A1F13A1F13AENSEMBLENSG00000124491Reactome Database ID Release 716789518Database 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=6789518ReactomeR-HSA-67895181Reactome 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-6789518.1ANXA1 geneReactome DB_ID: 6789507ENSEMBL:ENSG00000135046 ANXA1ANXA1ANX1LPC1ENSEMBLENSG00000135046Reactome Database ID Release 716789507Database 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=6789507ReactomeR-HSA-67895071Reactome 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-6789507.1LAMA5 geneReactome DB_ID: 6789499ENSEMBL:ENSG00000130702 LAMA5LAMA5KIAA0533KIAA1907ENSEMBLENSG00000130702Reactome Database ID Release 716789499Database 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=6789499ReactomeR-HSA-67894991Reactome 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-6789499.1COL1A2 geneReactome DB_ID: 6789344ENSEMBL:ENSG00000164692 COL1A2COL1A2ENSEMBLENSG00000164692Reactome Database ID Release 716789344Database 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=6789344ReactomeR-HSA-67893441Reactome 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-6789344.1CCL22 geneReactome DB_ID: 5660963ENSEMBL:ENSG00000102962 CCL22CCL17 geneCCL22MDCSCYA22A-152E5.1ENSEMBLENSG00000102962Reactome Database ID Release 715660963Database 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=5660963ReactomeR-HSA-56609631Reactome 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-5660963.1Reactome Database ID Release 716789505Database 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=6789505ReactomeR-HSA-67895052Reactome 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-6789505.2Converted from EntitySet in ReactomeIL4,IL13-upregulated extracellular proteinsReactome DB_ID: 6789504FNFN1(32-2386)FN1FibronectinCold-insoluble globulinCIGReactome DB_ID: 54851extracellular regionGENE ONTOLOGYGO:0005576UniProt:P02751 FN1FN1FNFUNCTION Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization. Participates in the regulation of type I collagen deposition by osteoblasts.FUNCTION Anastellin binds fibronectin and induces fibril formation. This fibronectin polymer, named superfibronectin, exhibits enhanced adhesive properties. Both anastellin and superfibronectin inhibit tumor growth, angiogenesis and metastasis. Anastellin activates p38 MAPK and inhibits lysophospholipid signaling.SUBUNIT Mostly heterodimers or multimers of alternatively spliced variants, connected by 2 disulfide bonds near the carboxyl ends; to a lesser extent homodimers. Interacts with FBLN1, AMBP, TNR, LGALS3BP and COL13A1. Interacts with FBLN7 (By similarity). Interacts with COMP (PubMed:12225811). Interacts with TNR; the interaction inhibits cell adhesion and neurite outgrowth (By similarity). Interacts with FST3 and MYOC.SUBUNIT (Microbial infection) Interacts with S.aureus FnbA.SUBUNIT (Microbial infection) Interacts with M.bovis FbpB via the collagen-binding region.SUBUNIT (Microbial infection) Interacts with recombinant S.pneumoniae PavA (rqcH).SUBUNIT (Microbial infection) Interacts with recombinant S.suis FbpS (rqcH) via fibronectin's N-terminal 30 kDa region.SUBUNIT (Microbial infection) Interacts with fibronectin-binding proteins from other Mycobacteria.TISSUE SPECIFICITY Expressed in the inner limiting membrane and around blood vessels in the retina (at protein level) (PubMed:29777959). Plasma FN (soluble dimeric form) is secreted by hepatocytes. Cellular FN (dimeric or cross-linked multimeric forms), made by fibroblasts, epithelial and other cell types, is deposited as fibrils in the extracellular matrix. Ugl-Y1, Ugl-Y2 and Ugl-Y3 are found in urine (PubMed:17614963).DEVELOPMENTAL STAGE Expressed between 12 and 19 weeks post-conception (WPC) in Bruch's membrane, with expression in the choroid evident from 14 WPC onwards (at protein level) (PubMed:29777959). Expressed in the inner limiting membrane at 17 WPC (at protein level) (PubMed:29777959). Ugl-Y1, Ugl-Y2 and Ugl-Y3 are present in the urine from 0 to 17 years of age (PubMed:17614963, PubMed:3584091).PTM Sulfated.PTM It is not known whether both or only one of Thr-2155 and Thr-2156 are/is glycosylated.PTM Forms covalent cross-links mediated by a transglutaminase, such as F13A or TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers (e.g. fibrinogen-fibronectin, collagen-fibronectin heteropolymers).PTM Phosphorylated by FAM20C in the extracellular medium.PTM Proteolytic processing produces the C-terminal NC1 peptide, anastellin.PTM Some lysine residues are oxidized to allysine by LOXL3, promoting fibronectin activation and matrix formation.UniProtP0275132EQUAL2386EQUALReactome Database ID Release 7154851Database 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=54851ReactomeR-HSA-548511Reactome 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-54851.1F13A1(1-731)factor XIII A chainReactome DB_ID: 140600UniProt:P00488 F13A1F13A1F13AFUNCTION Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl-epsilon-lysine cross-links between fibrin chains, thus stabilizing the fibrin clot. Also cross-link alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin.SUBUNIT Tetramer of two A chains (F13A1) and two B (F13B) chains.PTM The activation peptide is released by thrombin.POLYMORPHISM There are four main allelic forms of this protein; F13A*1A, F13A*1B, F13A*2A and F13A*2B. In addition two other intermediate forms (F13A*(2)A and F13A*(2)B) seem to exist. The sequence shown is that of F13A*(2)B.SIMILARITY Belongs to the transglutaminase superfamily. Transglutaminase family.UniProtP004881EQUAL731EQUALReactome Database ID Release 71140600Database 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=140600ReactomeR-HSA-1406001Reactome 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-140600.1ANXA1Annexin A1ANXA1_HUMANReactome DB_ID: 444539UniProt:P04083 ANXA1ANXA1ANX1LPC1FUNCTION Plays important roles in the innate immune response as effector of glucocorticoid-mediated responses and regulator of the inflammatory process. Has anti-inflammatory activity (PubMed:8425544). Plays a role in glucocorticoid-mediated down-regulation of the early phase of the inflammatory response (By similarity). Promotes resolution of inflammation and wound healing (PubMed:25664854). Functions at least in part by activating the formyl peptide receptors and downstream signaling cascades (PubMed:15187149, PubMed:25664854). Promotes chemotaxis of granulocytes and monocytes via activation of the formyl peptide receptors (PubMed:15187149). Contributes to the adaptive immune response by enhancing signaling cascades that are triggered by T-cell activation, regulates differentiation and proliferation of activated T-cells (PubMed:17008549). Promotes the differentiation of T-cells into Th1 cells and negatively regulates differentiation into Th2 cells (PubMed:17008549). Has no effect on unstimulated T cells (PubMed:17008549). Promotes rearrangement of the actin cytoskeleton, cell polarization and cell migration (PubMed:15187149). Negatively regulates hormone exocytosis via activation of the formyl peptide receptors and reorganization of the actin cytoskeleton (PubMed:19625660). Has high affinity for Ca(2+) and can bind up to eight Ca(2+) ions (By similarity). Displays Ca(2+)-dependent binding to phospholipid membranes (PubMed:2532504, PubMed:8557678). Plays a role in the formation of phagocytic cups and phagosomes. Plays a role in phagocytosis by mediating the Ca(2+)-dependent interaction between phagosomes and the actin cytoskeleton (By similarity).SUBUNIT Homodimer; non-covalently linked (By similarity). Homodimer; linked by transglutamylation (PubMed:2532504). Homodimers linked by transglutamylation are observed in placenta, but not in other tissues (PubMed:2532504). Interacts with S100A11 (PubMed:8557678, PubMed:10673436). Heterotetramer, formed by two molecules each of S100A11 and ANXA1 (PubMed:10673436). Interacts with DYSF (By similarity). Interacts with EGFR (By similarity).TISSUE SPECIFICITY Detected in resting neutrophils (PubMed:10772777). Detected in peripheral blood T-cells (PubMed:17008549). Detected in extracellular vesicles in blood serum from patients with inflammatory bowel disease, but not in serum from healthy donors (PubMed:25664854). Detected in placenta (at protein level) (PubMed:2532504). Detected in liver.DOMAIN The full-length protein can bind eight Ca(2+) ions via the annexin repeats. Calcium binding causes a major conformation change that modifies dimer contacts and leads to surface exposure of the N-terminal phosphorylation sites; in the absence of Ca(2+), these sites are buried in the interior of the protein core. The N-terminal region becomes disordered in response to calcium-binding.DOMAIN The N-terminal 26 amino acids are sufficient for its extracellular functions in the regulation of inflammation and wound healing (PubMed:25664854). Acylated peptides that contain the first 26 amino acids of the mature protein can activate signaling via the formyl peptide receptors (PubMed:15187149, PubMed:25664854).PTM Phosphorylated by protein kinase C, EGFR and TRPM7 (PubMed:2457390, PubMed:15485879). Phosphorylated in response to EGF treatment (PubMed:2532504).PTM Sumoylated.PHARMACEUTICAL Peptides based on the N-terminal sequence might be used for the treatment of inflammation, e.g. in chronic bowel diseases and in rheumatoid arthritis.MISCELLANEOUS Was originally identified as calcium and phospholipid binding protein that displays Ca(2+)-dependent binding to phospholipid membranes and can promote membrane aggregation in vitro. Was initially identified as inhibitor of phospholipase A2 activity (in vitro) (PubMed:2936963, PubMed:8425544). Inhibition of phospholipase activity is mediated via its phospholipid binding activity that limits the access of phospholipase to its substrates.SIMILARITY Belongs to the annexin family.UniProtP040832EQUAL346EQUALReactome Database ID Release 71444539Database 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=444539ReactomeR-HSA-4445391Reactome 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-444539.1LAMA5Laminin alpha-5 chainReactome DB_ID: 215956UniProt:O15230 LAMA5LAMA5KIAA0533KIAA1907FUNCTION Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.SUBUNIT Laminin is a complex glycoprotein, consisting of three different polypeptide chains (alpha, beta, gamma), which are bound to each other by disulfide bonds into a cross-shaped molecule comprising one long and three short arms with globules at each end. Alpha-5 is a subunit of laminin-10 (laminin-511), laminin-11 (laminin-521) and laminin-15 (laminin-523).TISSUE SPECIFICITY Expressed in heart, lung, kidney, skeletal muscle, pancreas, retina and placenta. Little or no expression in brain and liver.DOMAIN Domain G is globular and is part of the major cell-binding site located in the long arm of the laminin heterotrimer.UniProtO1523036EQUAL3695EQUALReactome Database ID Release 71215956Database 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=215956ReactomeR-HSA-2159561Reactome 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-215956.1CCL22CCL22(25-93)C-C motif chemokine 22CCL22_HUMANReactome DB_ID: 443980UniProt:O00626 CCL22CCL22MDCSCYA22A-152E5.1FUNCTION May play a role in the trafficking of activated/effector T-lymphocytes to inflammatory sites and other aspects of activated T-lymphocyte physiology. Chemotactic for monocytes, dendritic cells and natural killer cells. Mild chemoattractant for primary activated T-lymphocytes and a potent chemoattractant for chronically activated T-lymphocytes but has no chemoattractant activity for neutrophils, eosinophils, and resting T-lymphocytes. Binds to CCR4. Processed forms MDC(3-69), MDC(5-69) and MDC(7-69) seem not be active.TISSUE SPECIFICITY Highly expressed in macrophage and in monocyte-derived dendritic cells, and thymus. Also found in lymph node, appendix, activated monocytes, resting and activated macrophages. Lower expression in lung and spleen. Very weak expression in small intestine. In lymph node expressed in a mature subset of Langerhans' cells (CD1a+ and CD83+). Expressed in Langerhans' cell histiocytosis but not in dermatopathic lymphadenopathy. Expressed in atopic dermatitis, allergic contact dermatitis skin, and psoriasis, in both the epidermis and dermis.PTM The N-terminal processed forms MDC(3-69), MDC(5-69) and MDC(7-69) are produced by proteolytic cleavage after secretion from monocyte derived dendrocytes.SIMILARITY Belongs to the intercrine beta (chemokine CC) family.UniProtO0062625EQUAL93EQUALReactome Database ID Release 71443980Database 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=443980ReactomeR-HSA-4439801Reactome 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-443980.1COL1A2Collagen alpha-2(I) chainReactome DB_ID: 141093UniProt:P08123 COL1A2COL1A2FUNCTION Type I collagen is a member of group I collagen (fibrillar forming collagen).SUBUNIT Trimers of one alpha 2(I) and two alpha 1(I) chains.TISSUE SPECIFICITY Forms the fibrils of tendon, ligaments and bones. In bones the fibrils are mineralized with calcium hydroxyapatite.DOMAIN The C-terminal propeptide, also known as COLFI domain, have crucial roles in tissue growth and repair by controlling both the intracellular assembly of procollagen molecules and the extracellular assembly of collagen fibrils. It binds a calcium ion which is essential for its function.PTM Prolines at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains.DISEASE A chromosomal aberration involving COL1A2 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. Translocation t(7;8)(p22;q13) with PLAG1.SIMILARITY Belongs to the fibrillar collagen family.UniProtP0812380EQUAL1102EQUALReactome Database ID Release 71141093Database 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=141093ReactomeR-HSA-1410931Reactome 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-141093.1Reactome Database ID Release 716789504Database 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=6789504ReactomeR-HSA-67895041Reactome 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-6789504.1Reactome Database ID Release 716785895Database 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=6785895ReactomeR-HSA-67858952Reactome 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-6785895.215869882Pubmed2005Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and -13Chaitidis, PavlosO'Donnell, ValerieKuban, Ralf JBermudez-Fajardo, AlexandraUngethuem, UteKühn, HartmutCytokine 30:366-7715271999Pubmed2004Interleukin-13 stimulates the transcription of the human alpha2(I) collagen gene in human dermal fibroblastsJinnin, MasatoshiIhn, HironobuYamane, KenichiTamaki, KunihikoJ. Biol. Chem. 279:41783-9123124025Pubmed2013IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophagesBhattacharjee, AshishShukla, MeenakshiYakubenko, Valentin PMulya, AnnyKundu, SumanCathcart, Martha KFree Radic. Biol. Med. 54:1-1621252155Pubmed2011αMßâ‚‚ integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formationYakubenko, Valentin PBhattacharjee, AshishPluskota, ElzbietaCathcart, Martha KCirc. Res. 108:544-54ACTIVATIONReactome Database ID Release 716797277Database 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=6797277ReactomeR-HSA-67972771Reactome 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-6797277.1Converted from EntitySet in ReactomeIL4, IL13Reactome DB_ID: 6797283IL13Interleukin-13IL13_HUMANReactome DB_ID: 447211UniProt:P35225 IL13IL13NC30FUNCTION Cytokine (PubMed:8096327, PubMed:8097324). Inhibits inflammatory cytokine production (PubMed:8096327). Synergizes with IL2 in regulating interferon-gamma synthesis (PubMed:8096327). May be critical in regulating inflammatory and immune responses (PubMed:8096327, PubMed:8097324). Positively regulates IL31RA expression in macrophages (By similarity).SUBUNIT Interacts with IL13RA2.SIMILARITY Belongs to the IL-4/IL-13 family.CAUTION It is uncertain whether Met-1 or Met-15 is the initiator.UniProtP3522525EQUAL146EQUALReactome Database ID Release 71447211Database 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=447211ReactomeR-HSA-4472111Reactome 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-447211.1IL4Interleukin-4IL4_HUMANReactome DB_ID: 447110UniProt:P05112 IL4IL4FUNCTION Participates in at least several B-cell activation processes as well as of other cell types (PubMed:3016727). It is a costimulator of DNA-synthesis. It induces the expression of class II MHC molecules on resting B-cells. It enhances both secretion and cell surface expression of IgE and IgG1. It also regulates the expression of the low affinity Fc receptor for IgE (CD23) on both lymphocytes and monocytes. Positively regulates IL31RA expression in macrophages (By similarity). Stimulates autophagy in dendritic cells by interfering with mTORC1 signaling and through the induction of RUFY4 (By similarity).SIMILARITY Belongs to the IL-4/IL-13 family.UniProtP0511225EQUAL153EQUALReactome Database ID Release 71447110Database 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=447110ReactomeR-HSA-4471101Reactome 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-447110.1Reactome Database ID Release 716797283Database 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=6797283ReactomeR-HSA-67972831Reactome 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-6797283.1