ID GRB10_PIG Reviewed; 589 AA. AC B5KFD7; B5KFD3; B5KFD4; B5KFD6; DT 02-MAR-2010, integrated into UniProtKB/Swiss-Prot. DT 14-OCT-2008, sequence version 1. DT 24-JAN-2024, entry version 95. DE RecName: Full=Growth factor receptor-bound protein 10; DE AltName: Full=GRB10 adapter protein; GN Name=Grb10; OS Sus scrofa (Pig). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus. OX NCBI_TaxID=9823; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4). RA Nielsen A.L.; RT "Pig Grb10 is bi-alleic expressed."; RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases. CC -!- FUNCTION: Adapter protein which modulates coupling of a number of cell CC surface receptor kinases with specific signaling pathways. Binds to, CC and suppress signals from, activated receptors tyrosine kinases, CC including the insulin (INSR) and insulin-like growth factor (IGF1R) CC receptors. The inhibitory effect can be achieved by 2 mechanisms: CC interference with the signaling pathway and increased receptor CC degradation. Delays and reduces AKT1 phosphorylation in response to CC insulin stimulation. Blocks association between INSR and IRS1 and IRS2 CC and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. CC Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased CC internalization and degradation by both the proteasomal and lysosomal CC pathways. A similar role in the mediation of ubiquitination has also CC been suggested with INSR. Negatively regulates Wnt signaling by CC interacting with LRP6 intracellular portion and interfering with the CC binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 CC signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR- CC 2 (By similarity). {ECO:0000250}. CC -!- ACTIVITY REGULATION: Phosphorylation by mTORC1 stabilizes and activates CC GRB10 constituting a feedback pathway by which mTORC1 inhibits INSR- CC dependent signaling. {ECO:0000250}. CC -!- SUBUNIT: Interacts with ligand-activated tyrosine kinase receptors, CC including FGFR1, INSR, IGF1R, MET and PDGFRB in a phosphotyrosine- CC dependent manner through the SH2 domain. Poorly binds to the EGFR. CC Directly interacts with MAP3K14/NIK and is recruited to the EGFR-ERBB2 CC complex. Interacts with GIGYF1/PERQ1 and GIGYF2/TNRC15. When CC unphosphorylated, interacts with AKT1 and when phosphorylated with CC YWHAE/14-3-3 epsilon. Interacts with NEDD4. Interacts with LRP6, thus CC interfering with the binding of AXIN1 to LRP6. Binds relatively non- CC specifically to several phosphoinositides, including PI(5)P, PI(4,5)P2, CC PI(3,4)P2 and PI(3,4,5)P3, with modest affinities through the PH CC domain. Binds to activated NRAS (By similarity). {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=B5KFD7-1; Sequence=Displayed; CC Name=2; CC IsoId=B5KFD7-2; Sequence=VSP_038785; CC Name=3; CC IsoId=B5KFD7-3; Sequence=VSP_038785, VSP_038786, VSP_038787; CC Name=4; CC IsoId=B5KFD7-4; Sequence=VSP_038786, VSP_038787; CC -!- PTM: Phosphorylated on serine residues upon EGF, FGF and PDGF CC stimulation. {ECO:0000250}. CC -!- SIMILARITY: Belongs to the GRB7/10/14 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; EF174191; ABO93312.1; -; mRNA. DR EMBL; EF174192; ABO93313.1; -; mRNA. DR EMBL; EF174193; ABO93314.1; -; mRNA. DR EMBL; EF174194; ABO93315.1; -; mRNA. DR EMBL; EF174195; ABO93316.1; -; mRNA. DR EMBL; EF174196; ABO93317.1; -; mRNA. DR EMBL; EF174197; ABO93318.1; -; mRNA. DR EMBL; EF174198; ABO93319.1; -; mRNA. DR EMBL; EF174199; ABO93320.1; -; mRNA. DR RefSeq; NP_001128437.1; NM_001134965.1. [B5KFD7-1] DR AlphaFoldDB; B5KFD7; -. DR SMR; B5KFD7; -. DR STRING; 9823.ENSSSCP00000031279; -. DR PaxDb; 9823-ENSSSCP00000020573; -. DR Ensembl; ENSSSCT00000057201.2; ENSSSCP00000057939.2; ENSSSCG00000015631.5. [B5KFD7-4] DR Ensembl; ENSSSCT00000060494.2; ENSSSCP00000031279.1; ENSSSCG00000015631.5. [B5KFD7-1] DR Ensembl; ENSSSCT00015098893.1; ENSSSCP00015040822.1; ENSSSCG00015069263.1. [B5KFD7-2] DR Ensembl; ENSSSCT00025030811.1; ENSSSCP00025013000.1; ENSSSCG00025021300.1. [B5KFD7-1] DR Ensembl; ENSSSCT00025030952.1; ENSSSCP00025013047.1; ENSSSCG00025021300.1. [B5KFD7-3] DR Ensembl; ENSSSCT00030019333.1; ENSSSCP00030008610.1; ENSSSCG00030013785.1. [B5KFD7-1] DR Ensembl; ENSSSCT00030019392.1; ENSSSCP00030008631.1; ENSSSCG00030013785.1. [B5KFD7-3] DR Ensembl; ENSSSCT00035047394.1; ENSSSCP00035018961.1; ENSSSCG00035035590.1. [B5KFD7-1] DR Ensembl; ENSSSCT00035047412.1; ENSSSCP00035018970.1; ENSSSCG00035035590.1. [B5KFD7-3] DR Ensembl; ENSSSCT00045013453.1; ENSSSCP00045009288.1; ENSSSCG00045007886.1. [B5KFD7-1] DR Ensembl; ENSSSCT00045013635.1; ENSSSCP00045009423.1; ENSSSCG00045007886.1. [B5KFD7-3] DR Ensembl; ENSSSCT00050088371.1; ENSSSCP00050037878.1; ENSSSCG00050064694.1. [B5KFD7-1] DR Ensembl; ENSSSCT00050088439.1; ENSSSCP00050037911.1; ENSSSCG00050064694.1. [B5KFD7-3] DR Ensembl; ENSSSCT00055016172.1; ENSSSCP00055012722.1; ENSSSCG00055008083.1. [B5KFD7-1] DR Ensembl; ENSSSCT00055016340.1; ENSSSCP00055012872.1; ENSSSCG00055008083.1. [B5KFD7-3] DR Ensembl; ENSSSCT00060014480.1; ENSSSCP00060005616.1; ENSSSCG00060010913.1. [B5KFD7-1] DR Ensembl; ENSSSCT00065006754.1; ENSSSCP00065002952.1; ENSSSCG00065004787.1. [B5KFD7-1] DR Ensembl; ENSSSCT00065006762.1; ENSSSCP00065002957.1; ENSSSCG00065004787.1. [B5KFD7-3] DR Ensembl; ENSSSCT00070014564.1; ENSSSCP00070012027.1; ENSSSCG00070007353.1. [B5KFD7-1] DR Ensembl; ENSSSCT00070014581.1; ENSSSCP00070012040.1; ENSSSCG00070007353.1. [B5KFD7-1] DR Ensembl; ENSSSCT00070014664.1; ENSSSCP00070012115.1; ENSSSCG00070007353.1. [B5KFD7-3] DR GeneID; 100188977; -. DR KEGG; ssc:100188977; -. DR CTD; 2887; -. DR eggNOG; KOG3751; Eukaryota. DR GeneTree; ENSGT00940000155909; -. DR HOGENOM; CLU_023207_0_1_1; -. DR InParanoid; B5KFD7; -. DR OMA; QNGQHTR; -. DR OrthoDB; 3144731at2759; -. DR TreeFam; TF317511; -. DR Reactome; R-SSC-1433557; Signaling by SCF-KIT. DR Reactome; R-SSC-74713; IRS activation. DR Reactome; R-SSC-74749; Signal attenuation. DR Reactome; R-SSC-74751; Insulin receptor signalling cascade. DR Reactome; R-SSC-8853659; RET signaling. DR Reactome; R-SSC-9607240; FLT3 Signaling. DR Proteomes; UP000008227; Chromosome 9. DR Proteomes; UP000314985; Chromosome 9. DR Proteomes; UP000694570; Unplaced. DR Proteomes; UP000694571; Unplaced. DR Proteomes; UP000694720; Unplaced. DR Proteomes; UP000694722; Unplaced. DR Proteomes; UP000694723; Unplaced. DR Proteomes; UP000694724; Unplaced. DR Proteomes; UP000694725; Unplaced. DR Proteomes; UP000694726; Unplaced. DR Proteomes; UP000694727; Unplaced. DR Proteomes; UP000694728; Unplaced. DR Bgee; ENSSSCG00000015631; Expressed in muscle tissue and 41 other cell types or tissues. DR ExpressionAtlas; B5KFD7; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl. DR GO; GO:0005158; F:insulin receptor binding; IBA:GO_Central. DR GO; GO:0030159; F:signaling receptor complex adaptor activity; IEA:Ensembl. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0010467; P:gene expression; IEA:Ensembl. DR GO; GO:0008286; P:insulin receptor signaling pathway; IBA:GO_Central. DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IEA:Ensembl. DR GO; GO:0046325; P:negative regulation of glucose import; IEA:Ensembl. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IBA:GO_Central. DR GO; GO:0042326; P:negative regulation of phosphorylation; IEA:Ensembl. DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; IEA:Ensembl. DR GO; GO:0030949; P:positive regulation of vascular endothelial growth factor receptor signaling pathway; ISS:UniProtKB. DR GO; GO:1904738; P:vascular associated smooth muscle cell migration; IEA:Ensembl. DR CDD; cd01259; PH_APBB1IP; 1. DR CDD; cd10415; SH2_Grb10; 1. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1. DR Gene3D; 3.30.505.10; SH2 domain; 1. DR InterPro; IPR015042; BPS-dom. DR InterPro; IPR039664; GRB/APBB1IP. DR InterPro; IPR035037; Grb10_SH2. DR InterPro; IPR011993; PH-like_dom_sf. DR InterPro; IPR039665; PH_APBB1IP. DR InterPro; IPR001849; PH_domain. DR InterPro; IPR000159; RA_dom. DR InterPro; IPR000980; SH2. DR InterPro; IPR036860; SH2_dom_sf. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR PANTHER; PTHR11243; GROWTH FACTOR RECEPTOR-BOUND PROTEIN; 1. DR PANTHER; PTHR11243:SF4; GROWTH FACTOR RECEPTOR-BOUND PROTEIN 10; 1. DR Pfam; PF08947; BPS; 1. DR Pfam; PF00169; PH; 1. DR Pfam; PF00788; RA; 1. DR Pfam; PF00017; SH2; 1. DR PRINTS; PR00401; SH2DOMAIN. DR SMART; SM00233; PH; 1. DR SMART; SM00314; RA; 1. DR SMART; SM00252; SH2; 1. DR SUPFAM; SSF50729; PH domain-like; 1. DR SUPFAM; SSF55550; SH2 domain; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS50003; PH_DOMAIN; 1. DR PROSITE; PS50200; RA; 1. DR PROSITE; PS50001; SH2; 1. DR Genevisible; B5KFD7; SS. PE 2: Evidence at transcript level; KW Alternative splicing; Cytoplasm; Phosphoprotein; Reference proteome; KW SH2 domain. FT CHAIN 1..589 FT /note="Growth factor receptor-bound protein 10" FT /id="PRO_0000392073" FT DOMAIN 161..245 FT /note="Ras-associating" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00166" FT DOMAIN 285..394 FT /note="PH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145" FT DOMAIN 488..584 FT /note="SH2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191" FT REGION 1..51 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 77..107 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 99 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q13322" FT MOD_RES 145 FT /note="Phosphoserine; by MTOR, MAPK1 and MAPK3" FT /evidence="ECO:0000250|UniProtKB:Q13322" FT MOD_RES 413 FT /note="Phosphoserine; by MAPK1 and MAPK3; in vitro" FT /evidence="ECO:0000250|UniProtKB:Q13322" FT MOD_RES 423 FT /note="Phosphoserine; by MTOR and PKB/AKT1" FT /evidence="ECO:0000250|UniProtKB:Q13322" FT MOD_RES 426 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q60760" FT MOD_RES 471 FT /note="Phosphoserine; by MTOR, MAPK1 and MAPK3" FT /evidence="ECO:0000250|UniProtKB:Q13322" FT VAR_SEQ 1..59 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|Ref.1" FT /id="VSP_038785" FT VAR_SEQ 511..548 FT /note="LFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQT -> RCTRLQWPSS FT KSLQTISAGEGVEKKEPYDPVGGIAYSI (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|Ref.1" FT /id="VSP_038786" FT VAR_SEQ 549..589 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|Ref.1" FT /id="VSP_038787" SQ SEQUENCE 589 AA; 66386 MW; 7F7F32CC84042B4D CRC64; MALAGGPDSF LHHPYYQDQV EQTSPHHPRD LAGPGFPAQP DRLAPHQEDD VDLEALVNDM DASLESLCSA SETAPLLHNG QHARGPPPPG ARPLRPQASP RHRVPRSQPL HILAARRLQE EDQQFRTSSL PAIPNPFPEL CGPGSPPVLS PGSLPPGQAA AKQDVKVFSE DGTCKVVEIL ADMTARDLCQ LLVYRSHCVD DNSWTLVEHH PHLGLERGLE DHERVTQVQH TLASESKFLF RKNYAKYEFF KNPTNFFPEQ MVTWCQQSNG SQTQLLQNFL NSSSCPEIQG FLHVKELGRK SWKKLYVCLR RSGLYCSTKG ASKEPRHLQL LADLEDSSIF SLIAGRKQYG APTDYGFCIK PNRVRTEAKE LRLLCAEDEQ SRTCWMTAFR LLKYGMLLYQ NYRVPQQRKA VLSPFSAPVR SVSENSLVAM DFSGQTGRVI ENPAEAQSAA LEEGHAWRKR STRMNILGSQ SPLHPSTLST VIHRTQHWFH GRISREESHR IIKQQGLVDG LFLLRDSQSN PKAFVLTLCH HQKIKNFQIL PCEDDGQTFF SLDDGNTKFS DLIQLVDFYQ LNKGVLPCKL KHHCIRVAL //