GAB2_MOUSE
ID GAB2_MOUSE Reviewed; 665 AA.
AC Q9Z1S8; Q9R1X3;
DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 13-APR-2004, sequence version 2.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=GRB2-associated-binding protein 2;
DE AltName: Full=GRB2-associated binder 2;
DE AltName: Full=Growth factor receptor bound protein 2-associated protein 2;
DE AltName: Full=PH domain-containing adaptor molecule p97;
GN Name=Gab2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 2-5; 81-91; 251-270;
RP 277-293; 512-529; 630-635 AND 640-648, FUNCTION, PHOSPHORYLATION,
RP INTERACTION WITH GRB2; PTPN11 AND SHC1, AND TISSUE SPECIFICITY.
RX PubMed=9885561; DOI=10.1016/s1097-2765(00)80288-9;
RA Gu H., Pratt J.C., Burakoff S.J., Neel B.G.;
RT "Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic
RT cells, reveals a novel pathway for cytokine-induced gene activation.";
RL Mol. Cell 2:729-740(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, PHOSPHORYLATION,
RP DEPHOSPHORYLATION BY PTPN11, AND INTERACTION WITH GRB2; PTPN11 AND PI-3
RP KINASE.
RX PubMed=10068651;
RA Nishida K., Yoshida Y., Itoh M., Fukada T., Ohtani T., Shirogane T.,
RA Atsumi T., Takahashi-Tezuka M., Ishihara K., Hibi M., Hirano T.;
RT "Gab-family adapter proteins act downstream of cytokine and growth factor
RT receptors and T- and B-cell antigen receptors.";
RL Blood 93:1809-1816(1999).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=11449275; DOI=10.1038/35084076;
RA Gu H., Saito K., Klaman L.D., Shen J., Fleming T., Wang Y., Pratt J.C.,
RA Lin G., Lim B., Kinet J.-P., Neel B.G.;
RT "Essential role for Gab2 in the allergic response.";
RL Nature 412:186-190(2001).
RN [4]
RP FUNCTION, DISRUPTION PHENOTYPE, INTERACTION WITH TNFRSF11A, AND
RP PHOSPHORYLATION AT TYR-441.
RX PubMed=15750601; DOI=10.1038/nm1203;
RA Wada T., Nakashima T., Oliveira-dos-Santos A.J., Gasser J., Hara H.,
RA Schett G., Penninger J.M.;
RT "The molecular scaffold Gab2 is a crucial component of RANK signaling and
RT osteoclastogenesis.";
RL Nat. Med. 11:394-399(2005).
RN [5]
RP INTERACTION WITH SYK, LIPID-BINDING, AND MUTAGENESIS OF ARG-32.
RX PubMed=16456001; DOI=10.4049/jimmunol.176.4.2421;
RA Yu M., Lowell C.A., Neel B.G., Gu H.;
RT "Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit
RT signals from FcepsilonRI.";
RL J. Immunol. 176:2421-2429(2006).
RN [6]
RP FUNCTION.
RX PubMed=17374739; DOI=10.1182/blood-2006-11-060707;
RA Zhang Y., Diaz-Flores E., Li G., Wang Z., Kang Z., Haviernikova E.,
RA Rowe S., Qu C.-K., Tse W., Shannon K.M., Bunting K.D.;
RT "Abnormal hematopoiesis in Gab2 mutant mice.";
RL Blood 110:116-124(2007).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-261; THR-262; TYR-263 AND
RP TYR-290, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Mast cell;
RX PubMed=17947660; DOI=10.4049/jimmunol.179.9.5864;
RA Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y.,
RA Kawakami T., Salomon A.R.;
RT "Quantitative time-resolved phosphoproteomic analysis of mast cell
RT signaling.";
RL J. Immunol. 179:5864-5876(2007).
RN [8]
RP MUTAGENESIS OF ARG-32, AND PHOSPHORYLATION AT SER-211 AND THR-388.
RX PubMed=19172738; DOI=10.1038/emboj.2008.159;
RA Brummer T., Larance M., Herrera Abreu M.T., Lyons R.J., Timpson P.,
RA Emmerich C.H., Fleuren E.D.G., Lehrbach G.M., Schramek D., Guilhaus M.,
RA James D.E., Daly R.J.;
RT "Phosphorylation-dependent binding of 14-3-3 terminates signalling by the
RT Gab2 docking protein.";
RL EMBO J. 27:2305-2316(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-405, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Adapter protein which acts downstream of several membrane
CC receptors including cytokine, antigen, hormone, cell matrix and growth
CC factor receptors to regulate multiple signaling pathways. Regulates
CC osteoclast differentiation mediating the TNFRSF11A/RANK signaling. In
CC allergic response, it plays a role in mast cells activation and
CC degranulation through PI-3-kinase regulation. Also involved in the
CC regulation of cell proliferation and hematopoiesis.
CC {ECO:0000269|PubMed:10068651, ECO:0000269|PubMed:11449275,
CC ECO:0000269|PubMed:15750601, ECO:0000269|PubMed:17374739,
CC ECO:0000269|PubMed:9885561}.
CC -!- SUBUNIT: Interacts with HCK (By similarity). Interacts with SHC1; may
CC mediate interaction with receptors. Interacts with SYK. Interacts with
CC PI-3 kinase. Interacts with GRB2 (via SH3 2 domain). Interacts
CC (phosphorylated) with PTPN11. Interacts with TNFRSF11A (via cytoplasmic
CC domain). Interacts (phosphorylated) with 14-3-3 family proteins SFN,
CC YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; prevents interaction with
CC GRB2 and attenuates GAB2 signaling. {ECO:0000250,
CC ECO:0000269|PubMed:10068651, ECO:0000269|PubMed:15750601,
CC ECO:0000269|PubMed:16456001, ECO:0000269|PubMed:9885561}.
CC -!- INTERACTION:
CC Q9Z1S8; P25911: Lyn; NbExp=2; IntAct=EBI-641738, EBI-643537;
CC Q9Z1S8; P29351: Ptpn6; NbExp=2; IntAct=EBI-641738, EBI-2620699;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane
CC {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC {ECO:0000269|PubMed:10068651, ECO:0000269|PubMed:9885561}.
CC -!- DOMAIN: The SH3-binding motifs mediate interaction with SHC1 and GRB2.
CC -!- DOMAIN: The PH domain mediates phosphatidylinositol 3,4,5-trisphosphate
CC and phosphatidylinositol 3,4-bisphosphate binding.
CC -!- PTM: Phosphorylated upon EGF stimulation. Phosphorylated on tyrosine
CC residues by HCK upon IL6 signaling (By similarity). Phosphorylated on
CC tyrosine residue(s) by the thrombopoietin receptor (TPOR), stem cell
CC factor receptor (SCFR), and T-cell and B-cell antigen receptors, gp130,
CC IL-2R and IL-3R. Phosphorylated upon stimulation of TNFRSF11A/RANK by
CC TNFSF11/RANKL. {ECO:0000250, ECO:0000269|PubMed:10068651,
CC ECO:0000269|PubMed:15750601, ECO:0000269|PubMed:19172738,
CC ECO:0000269|PubMed:9885561}.
CC -!- PTM: Dephosphorylated by PTPN11.
CC -!- DISRUPTION PHENOTYPE: Mice are viable and healthy for up to 15 months.
CC However, they have reduced number of mast cells and develop
CC osteopetrosis. {ECO:0000269|PubMed:11449275,
CC ECO:0000269|PubMed:15750601}.
CC -!- SIMILARITY: Belongs to the GAB family. {ECO:0000305}.
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DR EMBL; AF104244; AAD05166.1; -; mRNA.
DR EMBL; AB018414; BAA76738.1; -; mRNA.
DR CCDS; CCDS85340.1; -.
DR AlphaFoldDB; Q9Z1S8; -.
DR SMR; Q9Z1S8; -.
DR CORUM; Q9Z1S8; -.
DR DIP; DIP-41351N; -.
DR IntAct; Q9Z1S8; 14.
DR MINT; Q9Z1S8; -.
DR STRING; 10090.ENSMUSP00000004622; -.
DR iPTMnet; Q9Z1S8; -.
DR PhosphoSitePlus; Q9Z1S8; -.
DR jPOST; Q9Z1S8; -.
DR MaxQB; Q9Z1S8; -.
DR PaxDb; Q9Z1S8; -.
DR PRIDE; Q9Z1S8; -.
DR ProteomicsDB; 267415; -.
DR MGI; MGI:1333854; Gab2.
DR eggNOG; KOG3751; Eukaryota.
DR InParanoid; Q9Z1S8; -.
DR PhylomeDB; Q9Z1S8; -.
DR Reactome; R-MMU-109704; PI3K Cascade.
DR Reactome; R-MMU-1257604; PIP3 activates AKT signaling.
DR Reactome; R-MMU-1433557; Signaling by SCF-KIT.
DR Reactome; R-MMU-2730905; Role of LAT2/NTAL/LAB on calcium mobilization.
DR Reactome; R-MMU-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-MMU-8853659; RET signaling.
DR Reactome; R-MMU-912526; Interleukin receptor SHC signaling.
DR Reactome; R-MMU-9607240; FLT3 Signaling.
DR Reactome; R-MMU-9674555; Signaling by CSF3 (G-CSF).
DR ChiTaRS; Gab2; mouse.
DR PRO; PR:Q9Z1S8; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q9Z1S8; protein.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; IDA:UniProtKB.
DR GO; GO:0043325; F:phosphatidylinositol-3,4-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0019903; F:protein phosphatase binding; ISO:MGI.
DR GO; GO:0035591; F:signaling adaptor activity; IBA:GO_Central.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; ISS:UniProtKB.
DR GO; GO:0016477; P:cell migration; IDA:MGI.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; IDA:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:MGI.
DR GO; GO:0030316; P:osteoclast differentiation; IMP:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0010634; P:positive regulation of epithelial cell migration; IMP:CACAO.
DR GO; GO:0043306; P:positive regulation of mast cell degranulation; IMP:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR046355; Gab1-4-like.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR PANTHER; PTHR45960; PTHR45960; 1.
DR Pfam; PF00169; PH; 1.
DR SMART; SM00233; PH; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cytoplasm; Direct protein sequencing; Membrane;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..665
FT /note="GRB2-associated-binding protein 2"
FT /id="PRO_0000050286"
FT DOMAIN 8..119
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT REGION 131..184
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 338..396
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 408..445
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 491..517
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 548..632
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 646..665
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 348..355
FT /note="SH3-binding"
FT /evidence="ECO:0000250"
FT MOTIF 499..508
FT /note="SH3-binding"
FT /evidence="ECO:0000250"
FT COMPBIAS 131..150
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 160..184
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 357..383
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 427..445
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 548..597
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 614..629
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 135
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 142
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 143
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 149
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 150
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 160
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 165
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:19172738"
FT MOD_RES 220
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 261
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17947660"
FT MOD_RES 262
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:17947660"
FT MOD_RES 263
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:17947660"
FT MOD_RES 275
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 278
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 282
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 284
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 290
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:17947660"
FT MOD_RES 328
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 365
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 382
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 388
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:19172738"
FT MOD_RES 402
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 405
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 420
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 441
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:15750601"
FT MOD_RES 469
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 532
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 612
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MOD_RES 632
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9UQC2"
FT MUTAGEN 32
FT /note="R->C: Impairs EGF-induced phosphorylation at S-211
FT and T-388 and binding to phosphatidylinositol 3,4,5-
FT trisphosphate and phosphatidylinositol 3,4-bisphosphate."
FT /evidence="ECO:0000269|PubMed:16456001,
FT ECO:0000269|PubMed:19172738"
FT CONFLICT 542
FT /note="N -> NS (in Ref. 1; AAD05166)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 665 AA; 73208 MW; E8955EE638174085 CRC64;
MSGGGGDDVV CTGWLRKSPP EKKLRRYAWK KRWFILRSGR MSGDPDVLEY YKNEHSKKPL
RIINLNLCEQ VDAGLTFNKK ELQDSFVFDI KTSERTFYLV AETEADMNKW VQSICQICGF
NQAEESTDSL RNLSSASHGP RSSPAEFSSS QHLLRERKSS APSHSSQPTL FTFEPPVSSH
MQPTLSTSAP QEYLYLHQCI SRRTENARSA SFSQGTRQKS DTAVQKLAQS NGHCINGVGG
QVHGFYSLPK PSRHNTEFKD STYDLPRSLA SHGHTKSSLT GSETDNEDVY TFKMPSNTLC
RELGDLLVDN MDVPTTPLSA YQIPRTFTLD KNHNAMTVAT PGDSAIAPPP RPPKPSQAET
SQWGSIQQRP PISENSRSVA ATIPRRNTLP AMDNSRLHRA SSCETYEYPA RGSGESASWS
AEPPGKTAVG RSNSASSDDN YVPMNPGSST LLAMERPGDN SQSVYIPMSP GPHHFDPLGY
PSTALPIHRG PSRGSEIQPP PVNRNLKPDR KAKPTPLDLR NNTVIDELPF KSPVTKSWSR
INHTFNSSSS QYCRPISTQS ITSTDSGDSE ENYVPMQNPV SASPVPSGTN SPAPKKSTGS
VDYLALDFQP GSPSPHRKPS TSSVTSDEKV DYVQVDKEKT QALQNTMQEW TDVRQSSEPS
KGAKL
