BioPAX pathway converted from "RUNX3 Regulates Immune Response and Cell Migration" in the Reactome database.RUNX3 Regulates Immune Response and Cell MigrationRUNX3-mediated transcription regulates development of immune system cells. RUNX3 is necessary for the development of innate lymphoid cells (ILCs) of ILC1 and ILC3 lineages, which reside in the mucosa and are involved in response to external pathogens. RUNX3 exerts its role in the development of ILC1 and ILC3 lineages by stimulating expression of the RORC (RORgamma) gene, encoding nuclear retinoid-related orphan receptor-gamma (Ebihara et al. 2015).<br>RUNX3 regulates transcription of integrin genes ITGAL (CD11a) and ITGA4 (CD49d), involved in transendothelial migration of leukocytes during immune and inflammatory responses as well as co-stimulation of T cells (Domniguez-Soto et al. 2005). The RUNX3 splicing isoform p33 lacks the Runt domain and is unable to transactivate integrin genes. The p33 isoform is induced during maturation of monocyte-derived dendritic cells (MDDC), leading to reduced expression of genes involved in inflammatory responses, such as IL8 (interleukin-8) (Puig-Kroger et al. 2010).<br>RUNX3 positively regulates transcription of the SPP1 (osteopontin) gene, which contributes to invasiveness of pancreatic cancer cells (Whittle et al. 2015).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31LEFT-TO-RIGHTRUNX3:CBFB binds the RORC gene promoterBased on studies in mice, the complex of RUNX3 and CBFB binds the promoter of the RORC (RORgamma) gene, encoding nuclear retinoid-related orphan receptor-gamma. The RUNX binding site TGTGGT is conserved between mouse and human RORC promoters. Mouse Runx3 is expressed in innate lymphoid cell lineages ILC1 and ILC3, but not ILC2 (Ebihara et al. 2015).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31RORC geneReactome DB_ID: 8948433nucleoplasmGENE ONTOLOGYGO:0005654ENSEMBL:ENSG00000143365 RORCRORCNR1F3RORGRZRGHomo sapiensNCBI Taxonomy9606ENSEMBLENSG00000143365Reactome Database ID Release 758948433Database 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=8948433ReactomeR-HSA-89484331Reactome 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-8948433.1Reactomehttp://www.reactome.orgRUNX3:CBFBReactome DB_ID: 8865463CBFBCore-binding factor subunit betaPolyomavirus enhancer-binding protein 2 beta subunitPEA2-betaPEBP2-betaSL3-3 enhancer factor 1 subunit betaSL3/AKV core-binding factor beta subunitPEBB_HUMANReactome DB_ID: 8865293UniProt:Q13951 CBFBCBFBFUNCTION Forms the heterodimeric complex core-binding factor (CBF) with RUNX family proteins (RUNX1, RUNX2, and RUNX3). RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation.SUBUNIT Heterodimer with RUNX1, RUNX2 and RUNX3. Interacts with COPRS. Found in a complex with PRMT5 and RUNX1.DISEASE A chromosomal aberration involving CBFB is associated with acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein that consists of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11.SIMILARITY Belongs to the CBF-beta family.UniProtQ139511EQUAL182EQUALReactome Database ID Release 758865293Database 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=8865293ReactomeR-HSA-88652931Reactome 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-8865293.11AML2RUNX3Runt-related transcription factor 3RUNX3_HUMANAcute myeloid leukemia 2 proteinCBF-alpha-3CBFA3AML-2Polyomavirus enhancer-binding protein 2 alpha C subunitPEA2-alpha CPEBP2-alpha CPEBP2A3SL3-3 enhancer factor 1 alpha C subunitSL3/AKV core-binding factor alpha C subunitReactome DB_ID: 8865393UniProt:Q13761 RUNX3RUNX3AML2CBFA3PEBP2A3FUNCTION Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (By similarity). May be involved in the control of cellular proliferation and/or differentiation. In association with ZFHX3, upregulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (By similarity).SUBUNIT Heterodimer with CBFB. RUNX3 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization (By similarity). Interacts with TLE1 and SUV39H1 (PubMed:9751710 and PubMed:16652147). The tyrosine phosphorylated form (via runt domain) interacts with SRC (via protein kinase domain)(PubMed:20100835). Interacts with FYN and LCK (PubMed:20100835). Interacts with FOXP3 (PubMed:17377532). Interacts with ZFHX3 (PubMed:20599712). Interacts with TBX21 (By similarity).TISSUE SPECIFICITY Expressed in gastric cancer tissues (at protein level).DOMAIN A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.PTM Phosphorylated on tyrosine residues by SRC. Phosphorylated by LCK and FYN.UniProtQ137611EQUAL415EQUALReactome Database ID Release 758865393Database 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=8865393ReactomeR-HSA-88653931Reactome 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-8865393.11Reactome Database ID Release 758865463Database 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=8865463ReactomeR-HSA-88654631Reactome 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-8865463.1RUNX3:CBFB:RORC geneReactome DB_ID: 894927811Reactome Database ID Release 758949278Database 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=8949278ReactomeR-HSA-89492781Reactome 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-8949278.1Reactome Database ID Release 758949276Database 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=8949276ReactomeR-HSA-89492762Reactome 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-8949276.226414766Pubmed2015Runx3 specifies lineage commitment of innate lymphoid cellsEbihara, TakashiSong, ChristinaRyu, Stacy HPlougastel-Douglas, BeatriceYang, LipingLevanon, DitsaGroner, YoramBern, Michael DStappenbeck, Thaddeus SColonna, MEgawa, TakeshiYokoyama, Wayne MNat. Immunol. 16:1124-33LEFT-TO-RIGHTRORC gene expression is stimulated by RUNX3:CBFBBased on mouse studies, binding of the RUNX3:CBFB heterodimer to the RUNX binding motif TGTGGT conserved between the mouse and human promoters of the RORC (RORgamma) gene, stimulates transcription of the RORC transcript variant 2 (RORC-2), also known as RORgT (RORgamma-t). In the ILC3 lineage of innate lymphoid cells in mice, expression of the Ahr transcription factor is positively indirectly regulated by Runx3, most likely through RORgT (Ebihara et al. 2015).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31RORgTRORC-2ROR-gamma-tReactome DB_ID: 8949306UniProt:P51449-2 RORCRORCNR1F3RORGRZRGFUNCTION Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively (PubMed:19965867, PubMed:22789990). Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A (PubMed:19965867). Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC and PCK1 (PubMed:19965867). Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (PubMed:19381306, PubMed:19965867, PubMed:22789990, PubMed:26160376, PubMed:20203100). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376).SUBUNIT Interacts (via AF-2 motif) with the coactivator NCOA2 (via LXXLL motif) (PubMed:20211758). Interacts with the corepressor NCOR1 (By similarity). Interacts with CRY1 (PubMed:22170608). Interacts (via AF-2 motif) with the coactivators NCOA1 and PPARGC1A (via LXXLL motif) (By similarity). Interacts (via AF-2 motif) with PROX1 (By similarity). Interacts with FOXP3 (PubMed:18368049). Interacts with NR0B2 (By similarity).TISSUE SPECIFICITY Isoform 1 is widely expressed in many tissues, including liver and adipose, and highly expressed in skeletal muscle. Isoform 2 is primarily expressed in immature thymocytes.INDUCTION Up-regulated in the state of obesity.DOMAIN The AF-2 (activation function-2) motif is required for recruiting coregulators containing LXXLL motifs such as NCOA1 and NCOA2.SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily.UniProt IsoformP51449-21EQUAL497EQUALReactome Database ID Release 758949306Database 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=8949306ReactomeR-HSA-89493061Reactome 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-8949306.1Reactome Database ID Release 758949301Database 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=8949301ReactomeR-HSA-89493013Reactome 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-8949301.3ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 758949304Database 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=8949304ReactomeR-HSA-89493041Reactome 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-8949304.1LEFT-TO-RIGHTRUNX3:CBFB binds the ITGAL gene,(ITGA4 gene) promoterRUNX3, presumably in complex with CBFB, binds the RUNX response element in the promoter of the ITGAL (CD11a) gene, encoding leukocyte integrin involved in transendothelial migration of leukocytes during immune and inflammatory responses as well as co-stimulation of T cells (Puig-Kroger et al. 2003, Dominguez-Soto et al. 2005). RUNX3, as well as RUNX1, may also be involved in regulation of integrin alpha 4 (ITGA4, also known as CD49d) expression. A RUNX binding site exists in the ITGA4 promoter, but the direct binding of RUNX transcription factors has not been demonstrated (Domniguez-Soto et al. 2005). Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Converted from EntitySet in ReactomeITGAL gene,(ITGA4 gene)Reactome DB_ID: 8949354ITGAL geneCD11a geneReactome DB_ID: 8949325ENSEMBL:ENSG00000005844 ITGALITGALCD11aCD11AENSEMBLENSG00000005844Reactome Database ID Release 758949325Database 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=8949325ReactomeR-HSA-89493251Reactome 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-8949325.1ITGA4 geneCD49d geneReactome DB_ID: 8949356ENSEMBL:ENSG00000115232 ITGA4ITGA4CD49dIntegrin subunit alpha 4CD49DENSEMBLENSG00000115232Reactome Database ID Release 758949356Database 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=8949356ReactomeR-HSA-89493561Reactome 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-8949356.1Reactome Database ID Release 758949354Database 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=8949354ReactomeR-HSA-89493541Reactome 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-8949354.1RUNX3:CBFB:ITGAL gene,(ITGA4 gene)RUNX3:CBFB:CD11a gene,(CD49d gene)Reactome DB_ID: 894932811Reactome Database ID Release 758949328Database 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=8949328ReactomeR-HSA-89493281Reactome 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-8949328.1Reactome Database ID Release 758949335Database 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=8949335ReactomeR-HSA-89493352Reactome 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-8949335.212855590Pubmed2003RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elementsPuig-Kröger, AmayaSanchez-Elsner, TilmanRuiz, NatividadAndreu, Enrique JProsper, FelipeJensen, Uffe BGil, JuanaErickson, PaulDrabkin, HarryGroner, YoramCorbí, Angel LBlood 102:3252-6116164020Pubmed2005RUNX3 regulates the activity of the CD11a and CD49d integrin gene promotersDomínguez-Soto, AngelesRelloso, MiguelVega, Miguel ACorbí, Angel LPuig-Kröger, AmayaImmunobiology 210:133-9LEFT-TO-RIGHTITGAL gene,(ITGA4 gene) expression is stimulated by RUNX3:CBFBTranscription of the ITGAL (CD11a) gene, is stimulated by binding of RUNX3, presumably in complex with CBFB, to the ITGAL promoter. ITGAL is a leukocyte integrin involved in transendothelial migration of leukocytes during immune and inflammatory responses as well as co-stimulation of T cells. RUNX3, as well as RUNX1, positively regulate integrin alpha 4 (ITGA4, also known as CD49d) expression. A RUNX binding site exists in the ITGA4 promoter, but the direct regulation by RUNX transcription factors has not been demonstrated (Domniguez-Soto et al. 2005). Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Converted from EntitySet in ReactomeITGAL,(ITGA4)Reactome DB_ID: 8949353ITGALIntegrin alpha-L precursorITAL_HUMANReactome DB_ID: 198013plasma membraneGENE ONTOLOGYGO:0005886UniProt:P20701 ITGALITGALCD11AFUNCTION Integrin ITGAL/ITGB2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. Integrin ITGAL/ITGB2 is a receptor for F11R (PubMed:11812992, PubMed:15528364). Integin ITGAL/ITGB2 is a receptor for the secreted form of ubiquitin-like protein ISG15; the interaction is mediated by ITGAL (PubMed:29100055). Involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated killing, and antibody dependent killing by granulocytes and monocytes. Contributes to natural killer cell cytotoxicity (PubMed:15356110). Involved in leukocyte adhesion and transmigration of leukocytes including T-cells and neutrophils (PubMed:11812992). Required for generation of common lymphoid progenitor cells in bone marrow, indicating a role in lymphopoiesis (By similarity). Integrin ITGAL/ITGB2 in association with ICAM3, contributes to apoptotic neutrophil phagocytosis by macrophages (PubMed:23775590).SUBUNIT Heterodimer of an alpha and a beta subunit (PubMed:12526797). The ITGAL alpha subunit associates with the ITGB2 beta subunit (PubMed:12526797). Interacts with THBD (PubMed:27055590).SUBUNIT (Microbial infection) Interacts with SARS-CoV Orf7a protein.TISSUE SPECIFICITY Leukocytes.DOMAIN The integrin I-domain (insert) is a VWFA domain (PubMed:2537322). Integrins with I-domains do not undergo protease cleavage. The I-domain is necessary and sufficient for interaction with ICAM1 and F11R (PubMed:15528364).PTM In resting T-cells, up to 40% of surface ITGAL is constitutively phosphorylated. Phosphorylation causes conformational changes needed for ligand binding and is necessary for activation by some physiological agents.SIMILARITY Belongs to the integrin alpha chain family.UniProtP2070126EQUAL1170EQUALReactome Database ID Release 75198013Database 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=198013ReactomeR-HSA-1980131Reactome 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-198013.1ITGA4Integrin alpha-4 ITA4_HUMANReactome DB_ID: 198007UniProt:P13612 ITGA4ITGA4CD49DFUNCTION Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are also receptors for VCAM1. Integrin alpha-4/beta-1 recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-4/beta-7 is also a receptor for MADCAM1. It recognizes the sequence L-D-T in MADCAM1. On activated endothelial cells integrin VLA-4 triggers homotypic aggregation for most VLA-4-positive leukocyte cell lines. It may also participate in cytolytic T-cell interactions with target cells. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415). ITGA4:ITGB1 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877).SUBUNIT Heterodimer of an alpha and a beta subunit. The alpha subunit can sometimes be cleaved into two non-covalently associated fragments. Alpha-4 associates with either beta-1 or beta-7. Alpha-4 interacts with PXN, LPXN, and TGFB1I1/HIC5. Interacts with CSPG4 through CSPG4 chondroitin sulfate glycosaminoglycan. Interacts with JAML; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling JAML homodimerization. ITGA4:ITGB1 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). Interacts with MDK (PubMed:15466886). ITGA4:ITGB1 interacts with MDK; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886).DOMAIN The SG1 motif is involved in binding to chondroitin sulfate glycosaminoglycan and cell adhesion.PTM Phosphorylation on Ser-1027 inhibits PXN binding.SIMILARITY Belongs to the integrin alpha chain family.UniProtP1361234EQUAL1032EQUALReactome Database ID Release 75198007Database 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=198007ReactomeR-HSA-1980071Reactome 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-198007.1Reactome Database ID Release 758949353Database 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=8949353ReactomeR-HSA-89493531Reactome 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-8949353.1Reactome Database ID Release 758949343Database 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=8949343ReactomeR-HSA-89493433Reactome 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-8949343.3ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 758951698Database 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=8951698ReactomeR-HSA-89516981Reactome 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-8951698.1LEFT-TO-RIGHTSPP1 gene expression is stimulated by RUNX3Both human and mouse SPP1 (osteopontin) gene promoters contain Runx and SMAD response elements. Transcription of SPP1 increases in response to increased RUNX3 levels, which contributes to invasiveness of pancreatic cancer cells. Direct binding of RUNX3 to the SPP1 promoter has not been examined (Whittle et al. 2015).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31SPP1 geneOsteopontin geneReactome DB_ID: 8952436ENSEMBL:ENSG00000118785 SPP1SPP1OsteopontinBNSPOPNPSEC0156ENSEMBLENSG00000118785Reactome Database ID Release 758952436Database 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=8952436ReactomeR-HSA-89524361Reactome 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-8952436.1SPP1Bone sialoprotein 1OsteopontinSecreted phosphoprotein 1Reactome DB_ID: 215967extracellular regionGENE ONTOLOGYGO:0005576UniProt:P10451 SPP1SPP1BNSPOPNPSEC0156FUNCTION Binds tightly to hydroxyapatite. Appears to form an integral part of the mineralized matrix. Probably important to cell-matrix interaction.FUNCTION Acts as a cytokine involved in enhancing production of interferon-gamma and interleukin-12 and reducing production of interleukin-10 and is essential in the pathway that leads to type I immunity.SUBUNIT Ligand for integrin alpha-V/beta-3.TISSUE SPECIFICITY Bone. Found in plasma.PTM Extensively phosphorylated by FAM20C in the extracellular medium at multiple sites within the S-x-E/pS motif.PTM O-glycosylated. Isoform 5 is GalNAc O-glycosylated at Thr-59 or Ser-62.SIMILARITY Belongs to the osteopontin family.UniProtP1045117EQUAL314EQUALReactome Database ID Release 75215967Database 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=215967ReactomeR-HSA-2159671Reactome 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-215967.1Reactome Database ID Release 758952442Database 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=8952442ReactomeR-HSA-89524424Reactome 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-8952442.426004068Pubmed2015RUNX3 Controls a Metastatic Switch in Pancreatic Ductal AdenocarcinomaWhittle, Martin CIzeradjene, KamelRani, P GeethaFeng, LibingCarlson, Markus ADelGiorno, Kathleen EWood, Laura DGoggins, MichaelHruban, Ralph HChang, Amy ECalses, PhilamerThorsen, Shelley MHingorani, Sunil RCell 161:1345-60ACTIVATIONReactome Database ID Release 758952449Database 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=8952449ReactomeR-HSA-89524491Reactome 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-8952449.1Reactome Database ID Release 758949275Database 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=8949275ReactomeR-HSA-89492751Reactome 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-8949275.120615577Pubmed2010The novel RUNX3/p33 isoform is induced upon monocyte-derived dendritic cell maturation and downregulates IL-8 expressionPuig-Kröger, AmayaAguilera-Montilla, NoemíMartínez-Nuñez, RocíoDomínguez-Soto, AngelesSánchez-Cabo, FátimaMartín-Gayo, EnriqueZaballos, AngelToribio, María LGroner, YoramIto, YoshiakiDopazo, AnaCorcuera, María TAlonso Martín, María JVega, Miguel ACorbí, Angel LImmunobiology 215:812-20