GAB2 (GRB2-associated binding protein 2)

2010-01-01   Tilman Brummer 

Centre for Biological Systems Analysis (ZBSA), Institute for Biology III, Cluster of Excellence 294 bioss, Albert-Ludwigs-University of Freiburg, Germany





The GAB2 gene is composed of 10 exons spanning a region of 222666 bp (see Mapping for details).


Not known.



PubMed predicts two distinct subtypes encoded by alternative transcripts. The variant GRB2-associated binding protein 2 isoform b contains an alternate exon 1 compared to transcript variant 1. It maintains the same reading frame, but encodes the shorter isoform (b), which lacks aa 1-38 of isoform a (for details see AA865573, AB011143).


Amino acids: 766. Calculated molecular mass: 74,327 kDa. However, presumably due to its richness in proline residues and its high degree of phosphorylation, GAB2 usually runs around 95 kDa in conventional SDS-PAGE gels. GAB2 protein isolated from cells stimulated via growth factors, cytokines or antigen receptors exhibit a prominent electrophoretic mobility shift, which reflects the high degree of feedback phosphorylation events at Ser/thr-residues.
This protein is a member of the GRB2-associated binding protein (GAB)/daughter-of-sevenless (DOS) family and is similar to the well studied GAB1 protein. These docking proteins contain pleckstrin homology (PH) domain, and are recruited to various receptors via small adaptor proteins such as the GRB2 adapter protein.


At low levels, GAB2 is presumably expressed in a wide range of tissues and cell types. Prominent expression is observed in various hematopoietic and neuronal lineages. Aberrant overexpression has been observed in various malignancies such as breast cancer, melanoma, acute myeloid leukemia, ovarian and gastric carcinoma.


Mainly cytoplasmic in unstimulated cells, however this protein is recruited to the plasmamembrane by various stimuli. This recruitment process requires either the PH domain and/or the small adaptor protein GRB2, either alone or in conjunction with adaptor proteins of the SHC family.


Gab/DOS proteins integrate and amplify signals from growth factor, cytokine and antigen receptors as well as from cell adhesion molecules. They also diversify signals by channelling the input information from activated receptors into signalling pathways with distinct biological functions. Gab proteins are subject to a complex regulation by feed-forward and feedback phosphorylation events as well as protein-protein interactions. Gab/DOS docking proteins organise entire signalling subsystems and thereby fulfil an important if not essential role in many physiological processes. GAB2 is implicated in various differentiation processes within the hematopoietic and nervous systems. In particular, GAB2 deficient mice display impaired osteoclast development and consequently display osteopetrosis. GAB2 is also essential for the FceRI-mediated degranulation of murine mast cells.
Aberrant expression and/or signalling by GAB2 has been increasingly linked to human diseases from various forms of neoplasia over inflammation to Alzheimers disease.
A detailed recent review on GAB2 can be found in Wohrle et al. (2009a).


The closest relative is the putative product of the GAB4 gene, followed by the well studied GAB1 and less studied GAB3 protein. Gab-like proteins have been also identified in Drosophila melanogaster (daughter-of-seveless (DOS)) and Caenorhabditis elegans (Suppressor-of-clear 1 (SOC1)).



No germinal mutations described.


One somatic missense mutation has been reported in the COSMIC database leading to replacement of P161 by a leucine residue. The functional consequences have not been addressed yet. For details see:

Implicated in

Entity name
Breast cancer
GAB2 is frequently over-expressed in human breast cancer cell lines and primary tumours. Overexpression of GAB2 has been shown to be an early event in breast cancer development. In response to EGF, insulin and bFGF stimulation, GAB2 becomes tyrosine phosphorylated indicating that these RTKs, which are implicated in breast cancer development or progression, use this docking protein to amplify their signals. There might be several, not necessarily mutually exclusive mechanisms by which GAB2 is up-regulated in breast cancer such as the amplification of the GAB2 locus, which resides in a region commonly amplified in breast cancers or the aberrant activity of the E2F transcription factor, which is often dysregulated in tumours and binds directly to the human GAB2 promoter. Furthermore, the expression of both GAB2 mRNA and protein is induced by estradiol in an estrogen receptor-dependent manner. Modelling GAB2 expression levels to those observed in breast cancer in the immortalised, but non-transformed, human mammary epithelial cell MCF-10A implies that overexpression of this docking protein contributes to various aspects of malignant transformation such as increased proliferation and reduced growth factor requirements.
Studies from various laboratories using the MCF-10A model system as well as transgenic mouse models suggest that GAB2 also cooperates with other oncogenes implicated in breast cancer development such as HER2 and SRC. Indeed, a recent study by Bocanegra et al. (2009) has shown that small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. These findings are in agreement with studies in MCF-10A cells in which ectopically expressed GAB2 affects these biological parameters via the same effector pathways. GAB2 knockdown also impaired the proliferation and survival in the BT474 cell line, which contains a ERBB2 amplification, consistent with previous studies implicating GAB2 as an important downstream effector of this receptor tyrosine kinase.
Entity name
Two recent studies implicate GAB2 in malignant melanoma. Firstly, Horst et al. (2009) have shown that the GAB2 gene is amplified and/or over-expressed in 11% and 50% of human metastatic melanomas, respectively. Moreover, Chernoff et al. (2009) demonstrated that GAB2 amplification is associated with melanoma arising from sun-protected sites and often occurs independently from oncogenic NRAS or BRAF mutations or amplification of the KIT gene. Importantly, knockdown and over-expression experiments revealed that GAB2 enhances the migratory and invasive behaviour of melanoma cells. In contrast to metastatic melanoma, normal human melanocyte lines, melanocytic nevi and primary melanomas displayed low GAB2 expression levels suggesting that GAB2 overexpression might represent a marker of neoplastic progression.
Entity name
Myeloid leukemias
The first evidence for a critical contribution of GAB2 to leukemogenesis was the observation that myeloid progenitors from GAB2-deficient mice are resistant to transformation by the BCR-ABL oncoprotein, which arises from a chromosomal translocation found in more than 90% of patients with chronic myeloid leukaemia (CML). Phosphorylation of Y177 within the BCR moiety leads to recruitment of the GRB2/GAB2 complex and downstream signalling via SHP2 and PI3K, two crucial events for enhanced proliferation and survival. Similarly, the oncogenic BCR-FGFR1 fusion protein, which consists of a BCR-derived moiety and the tyrosine kinase domain of the fibroblast growth factor receptor 1 (FGFR1), drives the tyrosine phosphorylation of GAB2 in murine bone marrow cells and their malignant transformation through phospho-Y177 mediated GRB2 association.
These findings suggest that GRB2-mediated recruitment of GAB2 to oncogenic fusion protein tyrosine kinases is a critical event for the induction of a CML-like disease.
The contribution of GAB2 to BCR-ABL signaling is further supported by the observation that shRNA-mediated silencing of endogenous GAB2 inhibits proliferation and colony formation of CD34+ cells from CML patients.
GAB2 is also involved in the pathogenesis of several other leukemias. The oncogenic fusion kinases TEL-ABL and TEL-JAK2 engage GAB2 in a similar manner as BCR-ABL.
The gene encoding the GAB2 interaction partner SHP2, represents the most common target of somatic mutations in juvenile myelomonocytic leukemia (JMML), a rare, albeit aggressive myelo-proliferative disorder occurring in children. The most frequently JMML-associated mutation, E76K, confers enhanced catalytic activity to SHP2 and requires GAB2 for transformation of primary murine myeloid progenitors.
Entity name
Other neoplasia
Amplification and/or over-expression of the human GAB2 gene has been also recently reported for ovarian and gastric carcinoma as well as for acute myeloid leukemia (AML). However, additional functional studies are needed to dissect the role that GAB2 plays in these malignancies.


Pubmed IDLast YearTitleAuthors
179989342008Gab2 and Src co-operate in human mammary epithelial cells to promote growth factor independence and disruption of acinar morphogenesis.Bennett HL et al
163695432006A role for the scaffolding adapter GAB2 in breast cancer.Bentires-Alj M et al
198087892009Genome-wide association studies in Alzheimer's disease.Bertram L et al
198815462010Focal amplification and oncogene dependency of GAB2 in breast cancer.Bocanegra M et al
183149092008Amplification of 11q13 in ovarian carcinoma.Brown LA et al
191727382008Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein.Brummer T et al
162539902006Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein.Brummer T et al
190150242009THOC5 couples M-CSF receptor signaling to transcription factor expression.Carney L et al
182723742008Association study of the GAB2 gene with the risk of developing Alzheimer's disease.Chapuis J et al
155743372004Transcriptional regulation of AKT activation by E2F.Chaussepied M et al
195091362009GAB2 amplifications refine molecular classification of melanoma.Chernoff KA et al
121407672002The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer.Daly RJ et al
118304912002Regulation of the Erk2-Elk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl(+) K562 leukemic cells by Gab2.Dorsey JF et al
200878602010Overexpression of the oncogenic signal transducer Gab2 occurs early in breast cancer development.Fleuren ED et al
178944132008Gab2 requires membrane targeting and the Met binding motif to promote lamellipodia, cell scatter, and epithelial morphogenesis downstream from the Met receptor.Frigault MM et al
98855611998Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation.Gu H et al
114492752001Essential role for Gab2 in the allergic response.Gu H et al
195238992009Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2.Harkiolaki M et al
193423742009Gab2-mediated signaling promotes melanoma metastasis.Horst B et al
191188192009The GAB2 gene and the risk of Alzheimer's disease: replication and meta-analysis.Ikram MA et al
173109892007Role of Gab2 in mammary tumorigenesis and metastasis.Ke Y et al
191719072009The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo.Kim HJ et al
175588592007Increased expression of Gab2, a scaffolding adaptor of the tyrosine kinase signalling, in gastric carcinomas.Lee SH et al
199245072010GAB2 is not associated with late-onset Alzheimer's disease in Chinese Han.Lin K et al
117824272002PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2.Lynch DK et al
170538332006PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2.Mao D et al
189507072009Grb2 associated binder 2 couples B-cell receptor to cell survival.Maus M et al
151431642004A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase.Million RP et al
198382082009The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer.Mira A et al
188548652009GAB2 is not associated with late-onset Alzheimer's disease in Japanese.Miyashita A et al
157103302005Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations.Mohi MG et al
192765442009Implication of GAB2 gene polymorphism in Italian patients with Alzheimer's disease.Nacmias B et al
175711622007Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling.Nakaoka Y et al
118613092002Requirement of Gab2 for mast cell development and KitL/c-Kit signaling.Nishida K et al
190498232009The c-Kit/D816V mutation eliminates the differences in signal transduction and biological responses between two isoforms of c-Kit.Pedersen M et al
175534212007GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.Reiman EM et al
121241772002Critical role for Gab2 in transformation by BCR/ABL.Sattler M et al
162783042006Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML).Scherr M et al
192041632009GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.Schjeide BM et al
188534602009Common variation in GRB-associated Binding Protein 2 (GAB2) and increased risk for Alzheimer dementia.Sleegers K et al
180713092008BCR-ABL oncogenic transformation of NIH 3T3 fibroblasts requires the IL-3 receptor.Tao WJ et al
157506012005The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis.Wada T et al
197373902009Function, regulation and pathological roles of the Gab/DOS docking proteins.Wöhrle FU et al
182350452008Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.Wu J et al
178047142007Genetic screening reveals an essential role of p27kip1 in restriction of breast cancer progression.Yuan Y et al
167364982006GAB2 is a novel target of 11q amplification in AML/MDS.Zatkova A et al
173747392007Abnormal hematopoiesis in Gab2 mutant mice.Zhang Y et al

Other Information

Locus ID:

NCBI: 9846
MIM: 606203
HGNC: 14458
Ensembl: ENSG00000033327


dbSNP: 9846
ClinVar: 9846
TCGA: ENSG00000033327


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Fc epsilon RI signaling pathwayKEGGko04664
Chronic myeloid leukemiaKEGGko05220
Fc epsilon RI signaling pathwayKEGGhsa04664
Chronic myeloid leukemiaKEGGhsa05220
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Ras signaling pathwayKEGGhsa04014
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by FGFR in diseaseREACTOMER-HSA-1226099
Signaling by FGFR1 in diseaseREACTOMER-HSA-5655302
FGFR1 mutant receptor activationREACTOMER-HSA-1839124
Signaling by cytosolic FGFR1 fusion mutantsREACTOMER-HSA-1839117
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Signal TransductionREACTOMER-HSA-162582
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G-protein beta:gamma signallingREACTOMER-HSA-397795
G beta:gamma signalling through PI3KgammaREACTOMER-HSA-392451
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
175534212007GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.191
175534212007GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.191
205347412010Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals.108
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
163695432006A role for the scaffolding adapter GAB2 in breast cancer.84
183149092008Amplification of 11q13 in ovarian carcinoma.56
157506012005The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis.47
182350452008Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.42
162539902006Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein.37
121407672002The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer.33


Tilman Brummer

GAB2 (GRB2-associated binding protein 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: