GAB2—a Scaffolding Protein in Cancer

Adams, Sarah J.; Aydin, Iraz T.; Çelebi, Jülide Tok

doi:10.1158/1541-7786.mcr-12-0352

Cited by 80 publications

(69 citation statements)

References 59 publications

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“…CCND1 , located on 11q13.2, has long been considered as the driving oncogene on the amplicon. However, the large size of the amplified region and narrow peaks that are telomeric and distinct from CCND1 suggest that several genes may be selected in this amplicon (Adams et al, 2012). Thus amplifications of 11q13-14.1 may involve both CCND1 and GAB2.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Signaling Adaptor Proteins

Luo

Hahn

2015

Journal of Genetics and Genomics

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Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

Oncogenic Signaling Adaptor Proteins

Luo

Hahn

2015

Journal of Genetics and Genomics

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“…As a consequence, Bcr-Abl organises a multimeric protein complex and activates various signalling pathways [11,12]. One critical signal transducer of Bcr-Abl and Grb2 interaction partner is the docking protein and proto-oncogene product Gab2 [13,14]. Grb2 is connected via its central SH2 domain to phospho-tyrosine 177 (Y177) in the Bcr moiety, while its C-terminal SH3 domain binds to a typical and an atypical Grb2 binding site in Gab2 [10,15,16].…”

Section: Introductionmentioning

confidence: 99%

Alterations of Gab2 signalling complexes in imatinib and dasatinib treated chronic myeloid leukaemia cells

et al. 2013

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BackgroundThe Gab2 docking protein acts as an important signal amplifier downstream of various growth factor receptors and Bcr-Abl, the driver of chronic myeloid leukaemia (CML). Despite the success of Bcr-Abl tyrosine kinase inhibitors (TKI) in the therapy of CML, TKI-resistance remains an unsolved problem in the clinic. We have recently shown that Gab2 signalling counteracts the efficacy of four distinct Bcr-Abl inhibitors. In the course of that project, we noticed that two clinically relevant drugs, imatinib and dasatinib, provoke distinct alterations in the electrophoretic mobility of Gab2, its signalling output and protein interactions. As the signalling potential of the docking protein is highly modulated by its phosphorylation status, we set out to obtain more insights into the impact of TKIs on Gab2 phosphorylation.FindingsUsing stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative mass spectrometry (MS), we show now that imatinib and dasatinib provoke distinct effects on the phosphorylation status and interactome of Gab2. This study identifies several new phosphorylation sites on Gab2 and confirms many sites previously known from other experimental systems. At equimolar concentrations, dasatinib is more effective in preventing Gab2 tyrosine and serine/threonine phosphorylation than imatinib. It also affects the phosphorylation status of more residues than imatinib. In addition, we also identify novel components of the Gab2 signalling complex, such as casein kinases, stathmins and PIP1 as well as known interaction partners whose association with Gab2 is disrupted by imatinib and/or dasatinib.ConclusionsBy using MS-based proteomics, we have identified new and confirmed known phosphorylation sites and interaction partners of Gab2, which may play an important role in the regulation of this docking protein. Given the growing importance of Gab2 in several tumour entities we expect that our results will help to understand the complex regulation of Gab2 and how this docking protein can contribute to malignancy.

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“…These results suggest that c-Kit/V560D can weakly activate downstream signaling through Grb2 and PI3 kinase leading to weaker activation of Akt and Erk signaling as well as weaker cell proliferation and survival. The adapter proteins Gab2 and SHC are important intermediates in the activation of both Akt and Erk [15,16], and the protein tyrosine phosphatase SHP2 is involved in Erk activation [17]. By using phospho-tyrosine antibodies, cKit/V560D was shown to be able to phosphorylate Gab2, SHC and SHP2 even in the absence of ligand stimulation and similar to Akt and Erk phosphorylation, phosphorylation of these three proteins was weaker than that of c-KIT/D816V expressing cells (Fig.…”

Section: Resultsmentioning

confidence: 91%

PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner

Lindblad

Kazi

Sun

2015

Cell. Mol. Life Sci.

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Oncogenic mutants of c-Kit are often found in mastocytosis, gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML). The activation mechanism of the most commonly occurring mutation, D816V in exon 17 of c-Kit, has been well-studied while other mutations remain fairly uncharacterized in this respect. In this study, we show that the constitutive activity of the exon 11 mutant V560D is weaker than the D816V mutant. Phosphorylation of downstream signaling proteins induced by the ligand for c-Kit, stem cell factor (SCF), was stronger in cKit/V560D expressing cells than in cells expressing c-kit/D816V. Although cells expressing cKit/V560D showed increased ligand-independent proliferation and survival compared to wildtype c-Kit expressing cells, these biological effects were weaker than in c-Kit/D816V expressing cells. In contrast to cells expressing wild-type c-Kit, cells expressing c-Kit/V560D were independent of Src family kinases for downstream signaling. However, the independence of Src family kinases was not due to a Src-like kinase activity that c-Kit/D816V displayed. Point mutations that selectively block the association of PI3 kinase with c-Kit/V560D inhibited ligandindependent activation of the receptor, while inhibition of the kinase activity of PI3 kinase with pharmacological inhibitors didn't affect the kinase activity of the receptor. This suggests a lipidkinase independent key role of PI3 kinase in c-Kit/V560D-mediated oncogenic signal transduction. Thus, PI3 kinase is an attractive therapeutic target in malignancies induced by c-Kit mutations independent of its lipid kinase activity.

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GAB2—a Scaffolding Protein in Cancer

Cited by 80 publications

References 59 publications

Oncogenic Signaling Adaptor Proteins

Oncogenic Signaling Adaptor Proteins

Alterations of Gab2 signalling complexes in imatinib and dasatinib treated chronic myeloid leukaemia cells

PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner

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