ISSN 1007-7626 CN 11-3870 / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology 2011 4 27 4 300 ~ 304 Gab2 * 310058 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 310058 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 1 2010-12-06 2010-01-25 No 2009R10005 * 0571-88208713 E-mail yke@ zju edu cn Received December 6 2010 Accepted January 25 2011 Supported by Zhejiang Qianjiang Talents Project No 2009R10005 * Corresponding author 0571-88208713 E-mail yke@ zju edu cn
4 Gab2 301 SH2 Src homology-2 PTB 1 Gab2 phospho-tyrosine binding GAB2 11q14 1 97 ~ 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-3 4 5-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 Gab2 10 11 Gab2 5 6 Grb2 Grb2 Gab2 IL2 Grb2 2 SH3 1 SH2 interleukin-2 IL3 interleukin-3 Grb2 SHC Src
302 27 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 2 2 1 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 2 2 2 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 Gab2 303 20% ~ 30% Gab2 16 ~ 18 10% ~ 15% estrogen receptor 25 Gab2 + ER + RhoA Ras homolog gene family member A 19 26 Gab2 Gab2 20 Gab2 27 Gab2 ErbB2 / Neu 20 21 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 21 24 Gab2 3 2 Gab2 ErbB2 / Neu Gab2 Gab2 MCF10A RAS-ERK PI3K-AKT Gab2
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