The multiple function of Grb2 associated binder (Gab) adaptor/scaffolding protein in immune cell signaling

Sármay, Gabriella; Angyal, Adrienn; Kertesz, Akos; Maus, Máté; Medgyesi, Dávid

doi:10.1016/j.imlet.2005.11.017

Cited by 71 publications

(54 citation statements)

References 51 publications

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“…25 Aside from a putative STAT5-binding site, Gab2 possesses multiple protein-binding motifs such as Src homology (SH)2 and SH3 domains, proline-rich repeats suitable for interaction with the p85a moiety of PI3K, as well as multiple tyrosine phosphorylation sites that may be targeted by kinases including Src family members. 35,36 Use of …”

Section: Discussionmentioning

confidence: 99%

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

Smyth

Phan

Wang

et al. 2011

Laboratory Investigation

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Interferon-g (IFNg) is an important immunoregulatory cytokine that can also decrease intestinal epithelial barrier function. Little is known about the intracellular signalling events immediately subsequent to IFNg/IFNg receptor interaction that mediate increases in epithelial permeability; data that could be used to ablate this effect of IFNg while leaving its immunostimulatory effects intact. This study assessed the potential involvement of Src family kinases in IFNg-induced increases in epithelial permeability using confluent filter-grown monolayers of the human colon-derived T84 epithelial cell line. Inhibition of Src kinase with the pharmacologic PP1 and use of Fyn kinase-specific siRNA significantly reduced IFNg-induced increases in epithelial permeability as gauged by translocation of noninvasive E. coli (HB101 strain) and flux of horseradish peroxidase (HRP) across monolayers of T84 cells. However, the drop in transepithelial resistance elicited by IFNg was not affected by either treatment. Immunoblotting revealed that IFNg activated the transcription factor STAT5 in T84 cells, and immunoprecipitation studies identified an IFNg-inducible interaction between STAT5b and the PI3K regulatory subunit p85a through formation of a complex requiring the adaptor molecule Gab2. siRNA targeting STAT5b and Gab2 reduced IFNg-induced increases in epithelial permeability and phosphorylation of PI3K(p85a). PP1 and Fyn siRNA reduced IFNg-induced PI3K activity (indicated by decreased phospho-Akt) and the formation of the STAT5b/PI3K(p85a) complex. Collectively, the results suggest the formation of a Fyn-dependent STAT5b/Gab2/PI3K complex that links IFNg to PI3K signalling and the regulation of macromolecular permeability in a model enteric epithelium.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

Smyth

Phan

Wang

et al. 2011

Laboratory Investigation

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“…Nevertheless, all sites must be removed to affect SNS function. Proteins that may interact with these phosphotyrosines include SH2-SH3 domain-containing adaptor proteins that have similar roles downstream of other membrane receptors (Birge et al 1996;Mccarty 1998;Sarmay et al 2006). Candidates include Crk, Dreadlocks (Dock)/Nck, and Downstream of receptor kinase (Drk), the Drosophila ortholog of Grb2.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Cell Adhesion Molecule Sticks-and-Stones Reveals Multiple Redundant Functional Domains, Protein-Interaction Motifs and Phosphorylated Tyrosines That Direct Myoblast Fusion in Drosophila melanogaster

Kocherlakota

McDermott

et al. 2008

Genetics

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The larval body wall muscles of Drosophila melanogaster arise by fusion of founder myoblasts (FMs) and fusion-competent myoblasts (FCMs). Sticks-and-Stones (SNS) is expressed on the surface of all FCMs and mediates adhesion with FMs and developing syncytia. Intracellular components essential for myoblast fusion are then recruited to these adhesive contacts. In the studies herein, a functional analysis of the SNS cytodomain using the GAL4/UAS system identified sequences that direct myoblast fusion, presumably through recruitment of these intracellular components. An extensive series of deletion and site-directed mutations were evaluated for their ability to rescue the myoblast fusion defects of sns mutant embryos. Deletion studies revealed redundant functional domains within SNS. Surprisingly, highly conserved consensus sites for binding post-synaptic density-95/discs large/zonula occludens-1-domain-containing (PDZ) proteins and serines with a high probability of phosphorylation play no significant role in myoblast fusion. Biochemical studies establish that the SNS cytodomain is phosphorylated at multiple tyrosines and their site-directed mutagenesis compromises the ability of the corresponding transgenes to rescue myoblast fusion. Similar mutagenesis revealed a requirement for conserved proline-rich regions. This complexity and redundancy of multiple critical sequences within the SNS cytodomain suggest that it functions through a complex array of interactions that likely includes both phosphotyrosine-binding and SH3-domain-containing proteins.

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“…GRB2-associated binding protein 2 (GAB2) is a scaffolding adapter protein that amplifies signaling from cytoplasmic and receptor tyrosine kinases by recruiting (with GRB2) signaling molecules such as SHP2 and the p85 subunit of phosphatidylinositol 3-kinase (PI3K) (Gu and Neel, 2003;Sarmay et al, 2006). GAB2 has been shown to be required for v-SEA and BCR/ABL-mediated transformation (Sattler et al, 2002;Ischenko et al, 2003).…”

Section: Chr 11 Gab2mentioning

confidence: 99%

Focal amplification and oncogene dependency of GAB2 in breast cancer

et al. 2009

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DNA amplifications in breast cancer are frequent on chromosome 11q, in which multiple driver oncogenes likely reside in addition to cyclin D1 (CCND1). One such candidate, the scaffolding adapter protein, GRB2-associated binding protein 2 (GAB2), functions in ErbB signaling and was recently shown to enhance mammary epithelial cell proliferation, and metastasis of ERBB2 (HER2/neu)-driven murine breast cancer. However, the amplification status and function of GAB2 in the context of amplification remain undefined. In this study, by genomic profiling of 172 breast tumors, and fluorescence in situ hybridization validation in an independent set of 210 scorable cases, we observed focal amplification spanning GAB2 (11q14.1) independent of CCND1 (11q13.2) amplification, consistent with a driver role. Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) 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. GAB2 knockdown also reduced proliferation and survival in a cell line (BT474) with ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate focal amplification of GAB2 in breast carcinogenesis, and underscore an oncogenic role of scaffolding adapter proteins, and a potential new point of therapeutic intervention.Oncogene ( Keywords: GAB2; DNA amplification; genomic profiling; array-based comparative genomic hybridization; breast cancer; oncogene dependency Breast cancer is the second leading cause of cancer death in women in the United States (Jemal et al., 2007), affecting all races and ethnicities. Breast cancer develops through multiple genetic alterations, including amplification and resultant overexpression of oncogenes. The discovery and characterization of amplified oncogenes informs the understanding of breast cancer pathogenesis, and provides useful biomarkers and therapeutic targets. This is best exemplified by ERBB2 (Her2/neu; 17q12), a receptor tyrosine kinase amplified in 20-30% of breast cancers and the target of molecularly directed therapies, such as trastuzumab (Pegram et al., 2000).The chromosomal region 11q13-q14 is amplified in 15-20% of breast cancers, and the finding of distinct loci amplified independently or in combination suggests the presence of multiple 'driver' oncogenes (Karlseder et al., 1994;Ormandy et al., 2003). Within the proximal (that is, more centromeric) region, cyclin D1 (CCND1; at 11q13.2) has been considered the main driver, promoting G1-to S-phase cell-cycle progression. Other candidate oncogenes frequently co-amplified at 11q13.2 include fibroblast growth factor-3 (also called int-2) and cortactin (EMSI) (Karlseder et al., 1994). More distally, EMSY (at 11q13.5), encoding a binding partner of breast cancer 2, early onset (BRCA2), has been nominated as an amplicon ...

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The multiple function of Grb2 associated binder (Gab) adaptor/scaffolding protein in immune cell signaling

Cited by 71 publications

References 51 publications

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

Analysis of the Cell Adhesion Molecule Sticks-and-Stones Reveals Multiple Redundant Functional Domains, Protein-Interaction Motifs and Phosphorylated Tyrosines That Direct Myoblast Fusion in Drosophila melanogaster

Focal amplification and oncogene dependency of GAB2 in breast cancer

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