BioPAX pathway converted from "Hyaluronidase 2 (HYAL2) hydrolyses HA into 20kDa fragments" in the Reactome database.LEFT-TO-RIGHT3.2.1.35Hyaluronidase 2 (HYAL2) hydrolyses HA into 20kDa fragmentsIn acidic conditions, hyaluronidase 2 (HYAL2), a membrane-anchored protein, hydrolyses high molecular weight HA into approximately 20kDa (50 disaccharide unit) fragments (Lepperdinger et al. 1998, Jedrzejas & Stern 2005).Authored: Jassal, B, 2012-03-05Reviewed: D'Eustachio, P, 2012-03-28Edited: Jassal, B, 2012-03-05HA:HAR:HYAL2:SLC9A1:pCHP:Ca2+Reactome DB_ID: 2160891plasma membraneGENE ONTOLOGYGO:0005886SLC9A1:p-CHP:Ca2+Reactome DB_ID: 5333682p-CHP1:Ca2+Reactome DB_ID: 5333752p-CHP1phosphorylated Calcineurin B homologous protein 1CHP1_HUMANReactome DB_ID: 5333747UniProt:Q99653 CHP1CHP1CHPFUNCTION Calcium-binding protein involved in different processes such as regulation of vesicular trafficking, plasma membrane Na(+)/H(+) exchanger and gene transcription. Involved in the constitutive exocytic membrane traffic. Mediates the association between microtubules and membrane-bound organelles of the endoplasmic reticulum and Golgi apparatus and is also required for the targeting and fusion of transcytotic vesicles (TCV) with the plasma membrane. Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Affects the pH sensitivity of SLC9A1/NHE1 by increasing its sensitivity at acidic pH. Required for the stabilization and localization of SLC9A1/NHE1 at the plasma membrane. Inhibits serum- and GTPase-stimulated Na(+)/H(+) exchange. Plays a role as an inhibitor of ribosomal RNA transcription by repressing the nucleolar UBF1 transcriptional activity. May sequester UBF1 in the nucleoplasm and limit its translocation to the nucleolus. Associates to the ribosomal gene promoter. Acts as a negative regulator of the calcineurin/NFAT signaling pathway. Inhibits NFAT nuclear translocation and transcriptional activity by suppressing the calcium-dependent calcineurin phosphatase activity. Also negatively regulates the kinase activity of the apoptosis-induced kinase STK17B. Inhibits both STK17B auto- and substrate-phosphorylations in a calcium-dependent manner.SUBUNIT Monomer. Interacts with STK17B; the interaction occurs in a calcium-independent manner and induces the translocation of CHP1 from the Golgi to the nucleus. Interacts with GAPDH; the interaction is direct, occurs in a N-myristoylation-dependent manner and facilitates the ability of CHP1 to bind microtubules. Interacts with KIF1B (via the C-terminal end of the kinesin-motor domain); the interaction occurs in a calcium-dependent manner. Associates (via C-terminal domain) with microtubules; the association occurs with polymerized microtubules during the cell cycle in a myristoylation- and calcium-independent manner and is enhanced by GAPDH (By similarity). Interacts with PPP3CA. Interacts with SLC9A1/NHE1 (via the juxtamembrane region of the cytoplasmic C-terminal domain); the interaction occurs at the plasma membrane in a calcium-dependent manner and at a domain that is critical for growth factor stimulation of the exchanger.TISSUE SPECIFICITY Ubiquitously expressed. Has been found in fetal eye, lung, liver, muscle, heart, kidney, thymus and spleen.PTM Phosphorylated; decreased phosphorylation is associated with an increase in SLC9A1/NHE1 Na(+)/H(+) exchange activity. Phosphorylation occurs in serum-dependent manner. The phosphorylation state may regulate the binding to SLC9A1/NHE1.PTM Both N-myristoylation and calcium-mediated conformational changes are essential for its function in exocytic traffic (By similarity). N-myristoylation is required for its association with microtubules and interaction with GAPDH, but not for the constitutive association to membranes.SIMILARITY Belongs to the calcineurin regulatory subunit family. CHP subfamily.Homo sapiensNCBI Taxonomy9606UniProtQ99653phosphorylated residueMODMOD:006962EQUAL195EQUALReactome Database ID Release 725333747Database 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=5333747ReactomeR-HSA-53337471Reactome 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-5333747.1Reactomehttp://www.reactome.org1Ca2+Calciumcalcium(2+)Reactome DB_ID: 140648calcium(2+) [ChEBI:29108]calcium(2+)ChEBICHEBI:29108Reactome Database ID Release 72140648Database 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=140648ReactomeR-ALL-1406484Reactome 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-140648.42Reactome Database ID Release 725333752Database 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=5333752ReactomeR-HSA-53337521Reactome 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-5333752.11NHE1SLC9A1Sodium/hydrogen exchanger 1SL9A1_HUMANReactome DB_ID: 426006UniProt:P19634 SLC9A1SLC9A1APNH1NHE1FUNCTION Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction.SUBUNIT Oligomer (By similarity). Interacts with CALM1 in a calcium-dependent manner (PubMed:12809501, PubMed:30287853). Interacts with TESC (PubMed:11696366, PubMed:30287853, PubMed:12809501). Interacts (via the juxtamembrane region of the cytoplasmic C-terminal domain) with CHP1; the interaction occurs at the plasma membrane in a calcium-dependent manner (PubMed:8967452, PubMed:8901634, PubMed:11350981, PubMed:15035633, PubMed:17050540). Interacts with CHP2; the interaction occurs in a calcium-dependent manner (PubMed:12226101, PubMed:16710297, PubMed:21392185).TISSUE SPECIFICITY Kidney and intestine.PTM O-glycosylated.PTM Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is reduced by CHP1 (By similarity).MISCELLANEOUS Inhibited by amiloride and 5-amino-substituted derivatives and activated in a cooperative fashion by intracellular H(+). In quiescent cells upon growth factor stimulation, the apparent affinity for internal H(+) is increased, resulting in a persistent rise in cytoplasmic pH.SIMILARITY Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.CAUTION The region between transmembrane regions M4 and M5 and between M6 and M7 (also termed intracellular loops IL2 and IL4, respectively) seem to be localized at least in part in the membrane. The hydrophobic region H10 is proposed to be located within the membrane.CAUTION Although PubMed:12809501 report that TESC-binding results in a decrease in activity, studies with rat SLC9A1 show that TESC-binding results in the maturation and accumulation of SLC9A1 at the cell surface.CAUTION The interacting region with TESC is conflicting: Interaction with TESC has been reported via the juxtamembrane region of the cytoplasmic C-terminal domain, including residues 503-545 (PubMed:11696366, PubMed:30287853). In contrast, another publication has reported interaction with TESC via residues 633-815, the region of the cytoplasmic C-terminus more distal to the membrane (PubMed:12809501).UniProtP196341EQUAL815EQUALReactome Database ID Release 72426006Database 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=426006ReactomeR-HSA-4260061Reactome 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-426006.11Reactome Database ID Release 725333682Database 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=5333682ReactomeR-HSA-53336821Reactome 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-5333682.11HA:HAR:HYAL2Reactome DB_ID: 2160889Converted from EntitySet in ReactomeHARsHA receptorsReactome DB_ID: 2160926CD44CD44 antigenCD44_HUMANHyaluronate receptorReactome DB_ID: 1031688UniProt:P16070 CD44CD44LHRMDU2MDU3MIC4FUNCTION Cell-surface receptor that plays a role in cell-cell interactions, cell adhesion and migration, helping them to sense and respond to changes in the tissue microenvironment (PubMed:16541107, PubMed:19703720, PubMed:22726066). Participates thereby in a wide variety of cellular functions including the activation, recirculation and homing of T-lymphocytes, hematopoiesis, inflammation and response to bacterial infection (PubMed:7528188). Engages, through its ectodomain, extracellular matrix components such as hyaluronan/HA, collagen, growth factors, cytokines or proteases and serves as a platform for signal transduction by assembling, via its cytoplasmic domain, protein complexes containing receptor kinases and membrane proteases (PubMed:18757307, PubMed:23589287). Such effectors include PKN2, the RhoGTPases RAC1 and RHOA, Rho-kinases and phospholipase C that coordinate signaling pathways promoting calcium mobilization and actin-mediated cytoskeleton reorganization essential for cell migration and adhesion (PubMed:15123640).SUBUNIT Interacts with PKN2 (PubMed:15123640). Interacts with TIAM1 and TIAM2 (By similarity). Interacts with HA, as well as other glycosaminoglycans, collagen, laminin, and fibronectin via its N-terminal segment (PubMed:14992719, PubMed:17085435, PubMed:25195884). Interacts with UNC119 (PubMed:19381274). Interacts with PDPN (via extracellular domain); this interaction is required for PDPN-mediated directional migration and regulation of lamellipodia extension/stabilization during cell spreading and migration (PubMed:20962267). Interacts with RDX, EZR and MSN (By similarity). Interacts with EGFR (PubMed:18757307, PubMed:23589287). Interacts with CD74; this complex is essential for the MIF-induced signaling cascade that results in B cell survival (By similarity).TISSUE SPECIFICITY Isoform 10 (epithelial isoform) is expressed by cells of epithelium and highly expressed by carcinomas. Expression is repressed in neuroblastoma cells.DEVELOPMENTAL STAGE Expressed in the developing retina between 16 and 19 weeks post-conception, specifically in the outer neuroblastic zone, inner neuroblastic zone, interphotoreceptor zone and the retinal pigment epithelium (at protein level).DOMAIN The lectin-like LINK domain is responsible for hyaluronan binding.PTM Proteolytically cleaved in the extracellular matrix by specific proteinases (possibly MMPs) in several cell lines and tumors.PTM N-glycosylated.PTM O-glycosylated. O-glycosylation contains more-or-less-sulfated chondroitin sulfate glycans, whose number may affect the accessibility of specific proteinases to their cleavage site(s). It is uncertain if O-glycosylation occurs on Thr-637 or Thr-638.PTM Phosphorylated; activation of PKC results in the dephosphorylation of Ser-706 (constitutive phosphorylation site), and the phosphorylation of Ser-672.POLYMORPHISM CD44 is responsible for the Indian blood group system. The molecular basis of the In(A)=In1/In(B)=In2 blood group antigens is a single variation in position 46; In(B), the most frequent allele, has Arg-46.UniProtP1607021EQUAL742EQUALReactome Database ID Release 721031688Database 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=1031688ReactomeR-HSA-10316881Reactome 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-1031688.1HMMRHyaluronan mediated motility receptorHMMR_HUMANReactome DB_ID: 2160885UniProt:O75330 HMMRHMMRIHABPRHAMMFUNCTION Receptor for hyaluronic acid (HA) (By similarity). Involved in cell motility (By similarity). When hyaluronan binds to HMMR, the phosphorylation of a number of proteins, including PTK2/FAK1 occurs. May also be involved in cellular transformation and metastasis formation, and in regulating extracellular-regulated kinase (ERK) activity. May act as a regulator of adipogenisis (By similarity).SUBUNIT Subunit of the HARC complex. Interacts with ANKRD26 (PubMed:22666460).TISSUE SPECIFICITY Expressed in breast cancer cell lines and in normal breast tissue.UniProtO753301EQUAL724EQUALReactome Database ID Release 722160885Database 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=2160885ReactomeR-HSA-21608851Reactome 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-2160885.1LYVE1Lymphatic vessel endothelial hyaluronic acid receptor 1LYVE1_HUMANReactome DB_ID: 2160921UniProt:Q9Y5Y7 LYVE1LYVE1CRSBP1HARXLKD1UNQ230/PRO263FUNCTION Ligand-specific transporter trafficking between intracellular organelles (TGN) and the plasma membrane. Plays a role in autocrine regulation of cell growth mediated by growth regulators containing cell surface retention sequence binding (CRS). May act as a hyaluronan (HA) transporter, either mediating its uptake for catabolism within lymphatic endothelial cells themselves, or its transport into the lumen of afferent lymphatic vessels for subsequent re-uptake and degradation in lymph nodes.SUBUNIT Homodimer; disulfide-linked. Interacts with PDGFB and IGFBP3. Forms a transient ternary complex with PDGFB and PDGFRB in TGN (By similarity).TISSUE SPECIFICITY Mainly expressed in endothelial cells lining lymphatic vessels.PTM O-glycosylated.UniProtQ9Y5Y720EQUAL322EQUALReactome Database ID Release 722160921Database 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=2160921ReactomeR-HSA-21609211Reactome 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-2160921.1HARESTAB2(1136-2551)STAB2Stabilin-2STAB2_HUMANHyaluronan receptor for endocytosis190 kDa form stabilin-2Reactome DB_ID: 2160853UniProt:Q8WWQ8 STAB2STAB2FEEL2FELLFEX2HAREFUNCTION Phosphatidylserine receptor that enhances the engulfment of apoptotic cells. Hyaluronan receptor that binds to and mediates endocytosis of hyaluronic acid (HA). Acts also, in different species, as a primary systemic scavenger receptor for heparin (Hep), chondroitin sulfate (CS), dermatan sulfate (DS), nonglycosaminoglycan (GAG), acetylated low-density lipoprotein (AcLDL), pro-collagen propeptides and advanced glycation end products (AGE). May serve to maintain tissue integrity by supporting extracellular matrix turnover or it may contribute to maintaining fluidity of bodily liquids by resorption of hyaluronan. Counter receptor which plays an important role in lymphocyte recruitment in the hepatic vasculature. Binds to both Gram-positive and Gram-negative bacteria and may play a role in defense against bacterial infection. The proteolytically processed 190 kDa form also functions as an endocytosis receptor for heparin internalisation as well as HA and CS.SUBUNIT Interacts with GULP1 and heparin. Also interacts with alpha-M/beta-2 integrin (ITGAM and ITGB2) and thymosin beta 4 (TMSB4X and/or TMSB4Y).TISSUE SPECIFICITY Highly expressed in sinusoidal endothelial cells of liver, spleen and lymph nodes. Also expressed in non SEC-cells such as HMDMs (monocyte-derivedmacrophages), HAMs (T-cell leukemia virus type 1-associated myelopathy), and several macrophage cell line.DOMAIN Recognizes phosphatidyl serine via its epidermal growth factor-like domains.PTM Glycosylated.PTM Proteolytically processed to yield a 190 kDa protein.UniProtQ8WWQ81136EQUAL2551EQUALReactome Database ID Release 722160853Database 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=2160853ReactomeR-HSA-21608531Reactome 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-2160853.1Reactome Database ID Release 722160926Database 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=2160926ReactomeR-HSA-21609261Reactome 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-2160926.11HYAL2Hyaluronidase-2HYAL2_HUMANReactome DB_ID: 2160919UniProt:Q12891 HYAL2HYAL2LUCA2FUNCTION Hydrolyzes high molecular weight hyaluronic acid to produce an intermediate-sized product which is further hydrolyzed by sperm hyaluronidase to give small oligosaccharides. Displays very low levels of activity. Associates with and negatively regulates MST1R.SUBUNIT Interacts with MST1R.TISSUE SPECIFICITY Widely expressed. No expression detected in adult brain.SIMILARITY Belongs to the glycosyl hydrolase 56 family.CAUTION Was originally thought to be lysosomal.UniProtQ1289121EQUAL448EQUALReactome Database ID Release 722160919Database 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=2160919ReactomeR-HSA-21609191Reactome 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-2160919.11HAHA polymerHyaluronanHyaluronic acidReactome DB_ID: 2160848extracellular regionGENE ONTOLOGYGO:0005576Reactome Database ID Release 722160848Database 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=2160848ReactomeR-ALL-21608482Reactome 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-2160848.21Reactome Database ID Release 722160889Database 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=2160889ReactomeR-HSA-21608891Reactome 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-2160889.11Reactome Database ID Release 722160891Database 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=2160891ReactomeR-HSA-21608912Reactome 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-2160891.2(HA)50Hyaluronic acidHyaluronanReactome DB_ID: 2160894Reactome Database ID Release 722160894Database 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=2160894ReactomeR-ALL-21608943Reactome 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-2160894.3ACTIVATIONactiveUnit: #Protein8GENE ONTOLOGYGO:0004415gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 722160850Database 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=2160850Reactome Database ID Release 722160892Database 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=2160892ReactomeR-HSA-21608921Reactome 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-2160892.19712871Pubmed1998HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificityLepperdinger, GStrobl, BKreil, GJ Biol Chem 273:22466-7016104017Pubmed2005Structures of vertebrate hyaluronidases and their unique enzymatic mechanism of hydrolysisJedrzejas, MJStern, RProteins 61:227-38