http / / cjbmb. bjmu. edu. cn Chinese Journal of Biochemistry and Molecular Biology Gab2 SHP2 / Ras / ERK PI3K / AKT Gab2 Signaling in Breast Cancer

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1 ISSN CN / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology ~ 304 Gab2 * Gab2 Gabs Gab2 SH2 SHP2 / Ras / ERK PI3K / AKT GAB2 ErbB2 / Neu Gab2 Gab2 Q291 Gab2 Signaling in Breast Cancer ZHANG Shan-Shan KE Yue-Hai * School of Medicine Zhejiang University Hangzhou China Abstract Gab2 is a key member of growth factor receptor-bound protein 2 Grb2 -associated binder Gab family proteins which transduces cellular signals between receptors and intracellular downstream effectors and provide platforms for protein interactions As a scaffolding adaptor Gab2 is usually activated by protein-tyrosine kinases PTKs integrating signals from a wide variety of extracellular stimuli When phosphorylated by PTKs Gab2 recruits several SH2 domain-containing proteins and subsequently triggers various downstream signal events such as SHP2 / Ras / ERK and PI3K / AKT playing an important role in cell growth differentiation apoptosis and migration Recently it has been reported that Gab2 is overexpressed in some primary mammary tumors and human breast cancer cell lines Gab2 mediated molecular events have been closely associated with mammary tumorigenesis and metastasis in coordination with oncogenic activities ErbB2 / Neu etc This review mainly focuses on the structure involvement in signal transduction of Gab2 protein and its regulation in breast cancer Key words scaffolding protein growth factor receptor-bound protein 2 Gab2 signal transduction breast cancer protein tyrosine kinases PTKs protein tyrosine phosphatases PTPs B / T No 2009R10005 * yke@ zju edu cn Received December Accepted January Supported by Zhejiang Qianjiang Talents Project No 2009R10005 * Corresponding author yke@ zju edu cn

2 4 Gab2 301 SH2 Src homology-2 PTB 1 Gab2 phospho-tyrosine binding GAB2 11q ~ 100 kd Gab2 3 N PH PRD proline-rich 25 7 Gabs Grb2-associated binder domain C Gab family proteins Fig 1 PH Gabs Gab1 ~ Gab4 DOS daughter of sevenless Ne-Gab phosphatidyl-inositol-phosphates PIPS PIP 3 Nematostella-Gab Soc1 suppressor of clear-1 3 Gab2 phosphatidylinositol-3 4-bisphosphate PI 4 5 P 2 PH pleckstrin homology phosphatidylinositol-4 5-bisphosphate 8 SH2 SH3 Src homology-3 phosphatidylinositol trisphosphate PI 3 4 P 2 Gab2 PRD PXXP Proline-rich sequences SH2 Gab2 SH3 Gabs SH3 Grb2 C 4-6 Gab2 GAB2 SH2 SHP2 SH2 Gab2 domain-containing protein-tyrosine phosphatase-2 Gab2 PI3K phosphatidyl-inositol-3-kinase p85 PLCγ phospholipase γ Crk Sarcoma virus CT10 oncogene homolog4 9 Fig 1 Structure of Gab2 scaffolding protein N-terminal PH domain is highly conversed its binding to PIPS is involved in membrane recruitment of Gab2 The central PRD contains numerous PXXP motifs mediating the interaction with SH3 domain-containing proteins such as Grb2 C-terminal multiple tyrosines are the binding sites for SH2-domain containing proteins such as SHP2 and p85 Grb2 SH2 2 Gab2 Gab2 2 Grb2 2 1 Gab2 PXXPXR Gab2 2 PX3RX2KP Grb2 2 PH SH3 Gab Gab2 5 6 Grb2 Grb2 Gab2 IL2 Grb2 2 SH3 1 SH2 interleukin-2 IL3 interleukin-3 Grb2 SHC Src

3 homology 2 domain-containing Gab2 Gab2 Grb2 SHC Gab2 12 SH2 SH3 SHP2 SH2 SHP2 2 2 Gab2 Gab2 Gab2 / SHP2 RAS / ERK SHP2 / Ras / ERK PI3K / AKT c-kit Gab2 Rac β1- PLCγ Crk GC-GAP Ras-GTPase activating protein STAT3 signal transducer and activator-3 STAT5 signal transducer and activator-5 Fig 2 Fig 2 Involvement of Gab2 protein in signal transduction 3 Characteristic of this mechanism is that the activated surface receptors serve as binding sites for SH2-domain of Grb2 which then binds to Gab2 via its SH3 domain Activated receptors lead to tyrosine phosphorylation of Gab2 protein and subsequent recruitment of SH2-domain containing effectors such as SHP2 p85 PLCγ Crk and STATs PH-domain confers recruitment of Gab2 to plasma membrane patches enriched in PIPS Gab2 3 YXXM PI3K SHP2 / Ras / ERK SHP2 Gab2 2 SH2 N SH2 C Gab2 protein tyrosine phosphatase PTP SHP2 3 1 Gab2 13 Gab2 2 SHP2 Gab2 acutemyeloid leukemia AML / bisphosphoryl tyrosine-based activation motif BTAM SHP2 2 SH2 14 Ras / ERK Gab2 PI3K PI3K / AKT GABs / PI3K Gab2 Gab2 p85 6 PI3K PIP S PIPS Gab2 PH Gab2 PI3K Gab2 9 B Gab1 / Gab2 SHP2 / ERK PI3K / AKT PI3K Gab2-SHP2 6 Gab2 / SHP2 / ERK PI3K 3 Gab2 Gab2 B / T Gab2 Gab2 Gab2 myelodysplastic syndrome MDS GAB2 SHP2 15

4 4 Gab % ~ 30% Gab2 16 ~ 18 10% ~ 15% estrogen receptor 25 Gab2 + ER + RhoA Ras homolog gene family member A Gab2 Gab2 20 Gab2 27 Gab2 ErbB2 / Neu GAB2 Gab2 Gab2 Daly 19 Gab2 Gab2 Gab2 Ras / ERK PI3K / AKT ER ER + Gab2 Gab2 Sf-STK SHP2 PTP11 2 PTP Gab2 Gab2 17 epidermal growth factor receptor EGFR human epidermal growth factor receptor HER ErbB2 Neu HER2 20 Ke 24 ErbB2 / Neu Src v-sea Gab2 SHP2 SHP2 PTPN11 EGFR 28 2 SHP2 ErbB3 HER3 ErbB4 HER4 SHP2 ErbB2 / Neu Gab2 / SHP2 22 ErbB2 / Neu 4 20% ~ 30% ErbB2 / Neu Gab2 23 Gab2 ErbB2 / Neu GAB2 ErbB2 / Neu Gabs Gab2 Gabs ErbB2 / Neu Gab2 Gab2 ErbB2 / Neu Gab2 3 2 Gab2 ErbB2 / Neu Gab2 Gab2 MCF10A RAS-ERK PI3K-AKT Gab2

5 GAB2 SHP2 J J Biol Chem 2001 Gab2 References 1 Ostman A Hellberg C Bohmer F D Protein-tyrosine phosphatases and cancer J Nat Rev Cancer Eulenfeld R Schaper F A new mechanism for the regulation of Gab1 recruitment to the plasma membrane J J Cell Sci Pt Wohrle F U Daly R J Brummer T Function regulation and pathological roles of the Gab / DOS docking proteins J Cell Commun Signal Nishida K Hirano T The role of Gab family scaffolding adapter proteins in the signal transduction of cytokine and growth factor receptors J Cancer Sci Gu H Neel B G The Gab in signal transduction J Trends Cell Biol Maus M Medgyesi D Kovesdi D et al Grb2 associated binder 2 couples B-cell receptor to cell survival J Cell Signal Pan X L Ren R J Wang G et al The Gab2 in signal transduction and its potential role in the pathogenesis of Alzheimer s disease J Neurosci Bull Franke T F PI3K / Akt getting it right matters J Oncogene Zhang T T Li H Cheung S M et al Phosphoinositide 3- kinase-regulated adapters in lymphocyte activation J Immunol Rev Lock L S Royal I Naujokas M A et al Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and-independent recruitment of Gab1 to receptor tyrosine kinases J J Biol Chem Harkiolaki M Tsirka T Lewitzky M et al Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2 J Structure Gu H Maeda H Moon J J et al New role for Shc in activation of the phosphatidylinositol 3-kinase / Akt pathway J Mol Cell Biol Neel B G Gu H Pao L The Shp ing news SH2 domaincontaining tyrosine phosphatases in cell signaling J Trends Biochem Sci Cunnick J M Mei L Doupnik C A et al Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif BTAM conferring binding and activation of Szepetowski P Ollendorff V Grosgeorge J et al DNA amplification at 11q13 5-q14 in human breast cancer J Oncogene Brown L A Kalloger S E Miller M A et al Amplification of 11q13 in ovarian carcinoma J Genes Chromosomes Cancer Bocanegra M Bergamaschi A Kim Y H et al Focal amplification and oncogene dependency of GAB2 in breast cancer J Oncogene Bekri S Adelaide J Merscher S et al Detailed map of a region commonly amplified at 11q13--> q14 in human breast carcinoma J Cytogenet Cell Genet Daly R J Gu H Parmar J et al The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer J Oncogene Fleuren E D O Toole S Millar E K et al Overexpression of the oncogenic signal transducer Gab2 occurs early in breast cancer development J Int J Cancer Bentires-Alj M Gil S G Chan R et al A role for the scaffolding adapter GAB2 in breast cancer J Nat Med Citri A Yarden Y EGF-ERBB signalling towards the systems level J Nat Rev Mol Cell Biol Slamon D J Leyland-Jones B Shak S et al Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 J N Engl J Med Ke Y Wu D Princen F et al Role of Gab2 in mammary tumorigenesis and metastasis J Oncogene Mira A Isella C Renzulli T et al The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer J Oncogene Abreu M T Hughes W E Mele K et al Gab2 regulates cytoskeletal organization and migration of mammary epithelial cells by modulating RhoA activation J Mol Biol Cell Frigault M M Naujokas M A Park M Gab2 requires membrane targeting and the Met binding motif to promote lamellipodia cell scatter and epithelial morphogenesis downstream from the Met receptor J J Cell Physiol Zhou X Coad J Ducatman B et al SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast implying its involvement in breast oncogenesis J Histopathology