Q9UQC2 (GAB2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
GRB2-associated-binding protein 2

Alternative name(s):
GRB2-associated binder 2
Growth factor receptor bound protein 2-associated protein 2
pp100

Gene names

Name:	GAB2
Synonyms:	KIAA0571

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	676 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways. Regulates osteoclast differentiation mediating the TNFRSF11A/RANK signaling. In allergic response, it plays a role in mast cells activation and degranulation through PI-3-kinase regulation. Also involved in the regulation of cell proliferation and hematopoiesis. Ref.8 Ref.9
Subunit structure	Interacts with SHC1; may mediate interaction with receptors By similarity. Interacts with SYK By similarity. Interacts with PI-3 kinase. Interacts with GRB2 (via SH3 2 domain). Interacts (phosphorylated) with PTPN11. Interacts with TNFRSF11A (via cytoplasmic domain). Interacts (phosphorylated) with 14-3-3 family proteins SFN, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; prevents interaction with GRB2 and attenuates GAB2 signaling. Interacts with HCK. Ref.1 Ref.7 Ref.8 Ref.9
Subcellular location	Cytoplasm. Cell membrane Ref.9.
Domain	The SH3-binding motifs mediate interaction with SHC1 and GRB2 By similarity. The PH domain mediates phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate binding By similarity.
Post-translational modification	Phosphorylated on tyrosine residue(s) by the thrombopoietin receptor (TPOR), stem cell factor receptor (SCFR), and T-cell and B-cell antigen receptors, gp130, IL-2R and IL-3R By similarity. Phosphorylated upon stimulation of TNFRSF11A/RANK by TNFSF11/RANKL By similarity. Phosphorylated upon EGF stimulation. Phosphorylated on tyrosine residues by HCK upon IL6 signaling. Ref.7 Ref.9 Dephosphorylated by PTPN11. Ref.7 Ref.9
Sequence similarities	Belongs to the GAB family. Contains 1 PH domain.
Sequence caution	The sequence BAA25497.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	osteoclast differentiation Inferred from mutant phenotype Ref.8. Source: UniProtKB phosphatidylinositol-mediated signaling Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell proliferation Inferred from direct assay Ref.9. Source: UniProtKB positive regulation of mast cell degranulation Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	cytosol Traceable author statement. Source: Reactome plasma membrane Inferred from direct assay Ref.9. Source: UniProtKB
Molecular_function	phosphatidylinositol-3,4,5-trisphosphate binding Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylinositol-3,4-bisphosphate binding Inferred from sequence or structural similarity. Source: UniProtKB transmembrane receptor protein tyrosine kinase adaptor activity Inferred from direct assay Ref.9. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GRB2	P62993	4	EBI-975200,EBI-401755

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9UQC2-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9UQC2-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-38: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 676

676

GRB2-associated-binding protein 2

PRO_0000050285

Regions

Domain

6 – 117

112

PH

Motif

351 – 358

8

SH3-binding

Motif

510 – 519

10

SH3-binding

Amino acid modifications

Modified residue

133

1

Phosphoserine Ref.9

Modified residue

140

1

Phosphoserine Ref.9

Modified residue

141

1

Phosphoserine Ref.9

Modified residue

148

1

Phosphoserine Ref.9

Modified residue

149

1

Phosphoserine Ref.9

Modified residue

159

1

Phosphoserine Ref.9

Modified residue

164

1

Phosphoserine Ref.9

Modified residue

210

1

Phosphoserine Ref.9

Modified residue

218

1

Phosphoserine Ref.9

Modified residue

223

1

Phosphoserine Ref.9

Modified residue

264

1

Phosphoserine Ref.9

Modified residue

265

1

Phosphothreonine By similarity

Modified residue

266

1

Phosphotyrosine By similarity

Modified residue

278

1

Phosphothreonine Ref.9

Modified residue

281

1

Phosphoserine Ref.9

Modified residue

287

1

Phosphothreonine Ref.9

Modified residue

293

1

Phosphotyrosine Ref.9

Modified residue

331

1

Phosphothreonine Ref.9

Modified residue

385

1

Phosphothreonine Ref.9

Modified residue

391

1

Phosphothreonine Ref.9

Modified residue

405

1

Phosphoserine Ref.9

Modified residue

452

1

Phosphotyrosine By similarity

Modified residue

480

1

Phosphoserine Ref.9

Modified residue

543

1

Phosphoserine Ref.9 Ref.10

Modified residue

622

1

Phosphoserine Ref.9

Modified residue

623

1

Phosphoserine Ref.9

Natural variations

Alternative sequence

1 – 38

38

Missing in isoform 2.

VSP_038520

Natural variant

320

1

P → L.
Corresponds to variant rs2279374 [ dbSNP | Ensembl ].

VAR_053097

Natural variant

344

1

P → L.
Corresponds to variant rs2279374 [ dbSNP | Ensembl ].

VAR_020407

Experimental info

Mutagenesis

210

1

S → A or E: Impaired interaction with 14-3-3 proteins and increased EGF-independent cell proliferation; when associated with A-391. Ref.9

Mutagenesis

391

1

T → A or E: Impaired interaction with 14-3-3 proteins and increased EGF-independent cell proliferation; when associated with A-210. Ref.9

Secondary structure

1

.

.

.

676

Helix Strand Turn

Details...

Helix

515 – 517

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 107623FD07D884C9	FASTA	676	74,458
	10 20 30 40 50 60 MSGGGDVVCT GWLRKSPPEK KLRRYAWKKR WFILRSGRMS GDPDVLEYYK NDHSKKPLRI 70 80 90 100 110 120 INLNFCEQVD AGLTFNKKEL QDSFVFDIKT SERTFYLVAE TEEDMNKWVQ SICQICGFNQ 130 140 150 160 170 180 AEESTDSLRN VSSAGHGPRS SPAELSSSSQ HLLRERKSSA PSHSSQPTLF TFEPPVSNHM 190 200 210 220 230 240 QPTLSTSAPQ EYLYLHQCIS RRAENARSAS FSQGTRASFL MRSDTAVQKL AQGNGHCVNG 250 260 270 280 290 300 ISGQVHGFYS LPKPSRHNTE FRDSTYDLPR SLASHGHTKG SLTGSETDNE DVYTFKTPSN 310 320 330 340 350 360 TLCREFGDLL VDNMDVPATP LSAYQIPRTF TLDKNHNAMT VATPGDSAIA PPPRPPKPSQ 370 380 390 400 410 420 AETPRWGSPQ QRPPISENSR SVAATIPRRN TLPAMDNSRL HRASSCETYE YPQRGGESAG 430 440 450 460 470 480 RSAESMSDGV GSFLPGKMIV GRSDSTNSED NYVPMNPGSS TLLAMERAGD NSQSVYIPMS 490 500 510 520 530 540 PGAHHFDSLG YPSTTLPVHR GPSRGSEIQP PPVNRNLKPD RKAKPTPLDL RNNTVIDELP 550 560 570 580 590 600 FKSPITKSWS RANHTFNSSS SQYCRPISTQ SITSTDSGDS EENYVPMQNP VSASPVPSGT 610 620 630 640 650 660 NSPAPKKSTG SVDYLALDFQ PSSPSPHRKP STSSVTSDEK VDYVQVDKEK TQALQNTMQE 670 WTDVRQSSEP SKGAKL
	Isoform 2 [UniParc]. Checksum: EA3BCC63C00BBAF0	FASTA	638	69,968
	10 20 30 40 50 60 MSGDPDVLEY YKNDHSKKPL RIINLNFCEQ VDAGLTFNKK ELQDSFVFDI KTSERTFYLV 70 80 90 100 110 120 AETEEDMNKW VQSICQICGF NQAEESTDSL RNVSSAGHGP RSSPAELSSS SQHLLRERKS 130 140 150 160 170 180 SAPSHSSQPT LFTFEPPVSN HMQPTLSTSA PQEYLYLHQC ISRRAENARS ASFSQGTRAS 190 200 210 220 230 240 FLMRSDTAVQ KLAQGNGHCV NGISGQVHGF YSLPKPSRHN TEFRDSTYDL PRSLASHGHT 250 260 270 280 290 300 KGSLTGSETD NEDVYTFKTP SNTLCREFGD LLVDNMDVPA TPLSAYQIPR TFTLDKNHNA 310 320 330 340 350 360 MTVATPGDSA IAPPPRPPKP SQAETPRWGS PQQRPPISEN SRSVAATIPR RNTLPAMDNS 370 380 390 400 410 420 RLHRASSCET YEYPQRGGES AGRSAESMSD GVGSFLPGKM IVGRSDSTNS EDNYVPMNPG 430 440 450 460 470 480 SSTLLAMERA GDNSQSVYIP MSPGAHHFDS LGYPSTTLPV HRGPSRGSEI QPPPVNRNLK 490 500 510 520 530 540 PDRKAKPTPL DLRNNTVIDE LPFKSPITKS WSRANHTFNS SSSQYCRPIS TQSITSTDSG 550 560 570 580 590 600 DSEENYVPMQ NPVSASPVPS GTNSPAPKKS TGSVDYLALD FQPSSPSPHR KPSTSSVTSD 610 620 630 EKVDYVQVDK EKTQALQNTM QEWTDVRQSS EPSKGAKL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors." Nishida K., Yoshida Y., Itoh M., Fukada T., Ohtani T., Shirogane T., Atsumi T., Takahashi-Tezuka M., Ishihara K., Hibi M., Hirano T. Blood 93:1809-1816(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH PTPN11. Tissue: Myeloma.
[2]	"Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro." Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 5:31-39(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Brain.
[3]	Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION.
[4]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
[7]	"Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells." Podar K., Mostoslavsky G., Sattler M., Tai Y.T., Hayashi T., Catley L.P., Hideshima T., Mulligan R.C., Chauhan D., Anderson K.C. J. Biol. Chem. 279:21658-21665(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY HCK, INTERACTION WITH HCK; CRKL PTPN11 AND GRB2.
[8]	"The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis." Wada T., Nakashima T., Oliveira-dos-Santos A.J., Gasser J., Hara H., Schett G., Penninger J.M. Nat. Med. 11:394-399(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TNFRSF11A.
[9]	"Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein." Brummer T., Larance M., Herrera Abreu M.T., Lyons R.J., Timpson P., Emmerich C.H., Fleuren E.D.G., Lehrbach G.M., Schramek D., Guilhaus M., James D.E., Daly R.J. EMBO J. 27:2305-2316(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH EGFR; GRB2; PTPN11; PI-3 KINASE; SFN; SHC1; YWHAB; YWHAE; YWHAG; YWHAH; YWHAQ AND YWHAZ, MUTAGENESIS OF SER-210 AND THR-391, PHOSPHORYLATION AT SER-133; SER-140; SER-141; SER-148; SER-149; SER-159; SER-164; SER-210; SER-218; SER-223; SER-264; THR-278; SER-281; THR-287; TYR-293; THR-331; THR-385; THR-391; SER-405; SER-480; SER-543; SER-622 AND SER-623.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-543, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[12]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2." Harkiolaki M., Tsirka T., Lewitzky M., Simister P.C., Joshi D., Bird L.E., Jones E.Y., O'Reilly N., Feller S.M. Structure 17:809-822(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 350-358 IN COMPLEX WITH GRB2, X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 508-522 IN COMPLEX WITH GRB2.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB018413 mRNA. Translation: BAA76737.1.
AB011143 mRNA. Translation: BAA25497.2. Different initiation.
AP002985 Genomic DNA. No translation available.
CH471076 Genomic DNA. Translation: EAW75057.1.
CH471076 Genomic DNA. Translation: EAW75058.1.
BC131711 mRNA. Translation: AAI31712.1.
BC152459 mRNA. Translation: AAI52460.1.

IPI

IPI00186990.
IPI00749276.

RefSeq

NP_036428.1. NM_012296.3.
NP_536739.1. NM_080491.2.

UniGene

Hs.429434.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2VWF	X-ray	1.58	B	508-522	[»]
2W0Z	X-ray	1.70	B	350-358	[»]

ProteinModelPortal

Q9UQC2.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-36653N.

IntAct

Q9UQC2. 5 interactions.

MINT

MINT-123618.

STRING

9606.ENSP00000302452.

PTM databases

PhosphoSite

Q9UQC2.

Polymorphism databases

DMDM

46396035.

Proteomic databases

PaxDb

Q9UQC2.

PRIDE

Q9UQC2.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000340149; ENSP00000343959; ENSG00000033327.
ENST00000361507; ENSP00000354952; ENSG00000033327.

GeneID

9846.

KEGG

hsa:9846.

UCSC

uc001ozg.3. human.

Organism-specific databases

CTD

9846.

GeneCards

GC11M077926.

HGNC

HGNC:14458. GAB2.

HPA

CAB022159.
HPA000271.

MIM

606203. gene.

neXtProt

NX_Q9UQC2.

PharmGKB

PA28478.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG83177.

HOGENOM

HOG000236270.

HOVERGEN

HBG051685.

KO

K08091.

OMA

VDNMDVP.

OrthoDB

EOG4HMJ8S.

PhylomeDB

Q9UQC2.

Enzyme and pathway databases

Pathway_Interaction_DB

fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
il2_pi3kpathway. IL2 signaling events mediated by PI3K.
il2_stat5pathway. IL2 signaling events mediated by STAT5.
il2_1pathway. IL2-mediated signaling events.
il6_7pathway. IL6-mediated signaling events.
trkrpathway. Neurotrophic factor-mediated Trk receptor signaling.
tcrpathway. TCR signaling in naive CD4+ T cells.

Reactome

REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q9UQC2.

Bgee

Q9UQC2.

CleanEx

HS_GAB2.

Genevestigator

Q9UQC2.

GermOnline

ENSG00000033327. Homo sapiens.

Family and domain databases

Gene3D

2.30.29.30. 1 hit.

InterPro

IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
[Graphical view]

Pfam

PF00169. PH. 1 hit.
[Graphical view]

SMART

SM00233. PH. 1 hit.
[Graphical view]

PROSITE

PS50003. PH_DOMAIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

GAB2. human.

EvolutionaryTrace

Q9UQC2.

GenomeRNAi

9846.

NextBio

37106.

SOURCE

Search...

Entry information

Entry name

GAB2_HUMAN

Accession

Primary (citable) accession number: Q9UQC2
Secondary accession number(s): A2RRM2 , A6NEW9, A7MD36, O60317

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 13, 2004
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 102 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.