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Benjamin G Neel - One of the best experts on this subject based on the ideXlab platform.
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Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1.
Blood, 2016Co-Authors: Wayne W. Chan, Benjamin G Neel, Golam Mohi, Joel C. Rosenbaum, Azin Sayad, Carl Virtanen, Richard A. Van EttenAbstract:Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph(+)B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GRB2-associated binding protein 2 (GAB2) as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transducedGAB2(-/-)bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors phosphatidylinositol 3-kinase (PI3K) or SRC homology 2-containing phosphotyrosine phosphatase 2 (SHP2). GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph(+)hematologic neoplasms.
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the scaffolding adapter GAB2 via shp 2 regulates kit evoked mast cell proliferation by activating the rac jnk pathway
Journal of Biological Chemistry, 2006Co-Authors: Jincai Luo, Yongping Wang, Wentian Yang, Masao Mizuki, Yuzuru Kanakura, Peter Besmer, Benjamin G NeelAbstract:Abstract The scaffolding adapter GAB2 mediates cell signaling and responses evoked by various extracellular stimuli including several growth factors. Kit, the receptor for stem cell factor (SCF), plays a critical role in the proliferation and differentiation of a variety of cell types, including mast cells. Kit, via Tyr567 and Tyr719, activates Src family kinases (SFK) and PI3K respectively, which converge on the activation of a Rac/JNK pathway required for mast cell proliferation. However, how Kit Tyr567 signals to Rac/JNK is not well understood. By analyzing GAB2–/– mast cells, we find that GAB2 is required for SCF-evoked proliferation, activation of Rac/JNK, and Ras. Upon Kit activation in wild-type mast cells, GAB2 becomes tyrosyl-phosphorylated and associates with Kit and Shp-2. Tyr567, an SFK binding site in Kit, and SFK activity were required for GAB2 tyrosyl phosphorylation and association with Shp-2. By re-expressing GAB2 or a GAB2 mutant that cannot bind Shp-2 in GAB2–/– mast cells or acutely by deleting Shp-2 in mast cells, we found that GAB2 requires Shp-2 for SCF-evoked Rac/JNK, Ras activation, and mast cell proliferation. Lastly, by analyzing mast cells from mice with compound GAB2 and Kit Y719F mutations (i.e., GAB2–/–: KitY719F/Y719F mice), we find that GAB2, acting in a parallel pathway to PI3K from Kit Tyr719, regulates mast cell proliferation and development in specific tissues. Our data show that GAB2 via Shp-2 is critical for transmitting signals from Kit Tyr567 to activate the Rac/JNK pathway controlling mast cell proliferation, which likely contributes to mast cell development in specific tissues.
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The Scaffolding Adapter GAB2, via Shp-2, Regulates Kit-evoked Mast Cell Proliferation by Activating the Rac/JNK Pathway
The Journal of biological chemistry, 2006Co-Authors: Jincai Luo, Yongping Wang, Wentian Yang, Masao Mizuki, Yuzuru Kanakura, Peter Besmer, Benjamin G NeelAbstract:Abstract The scaffolding adapter GAB2 mediates cell signaling and responses evoked by various extracellular stimuli including several growth factors. Kit, the receptor for stem cell factor (SCF), plays a critical role in the proliferation and differentiation of a variety of cell types, including mast cells. Kit, via Tyr567 and Tyr719, activates Src family kinases (SFK) and PI3K respectively, which converge on the activation of a Rac/JNK pathway required for mast cell proliferation. However, how Kit Tyr567 signals to Rac/JNK is not well understood. By analyzing GAB2–/– mast cells, we find that GAB2 is required for SCF-evoked proliferation, activation of Rac/JNK, and Ras. Upon Kit activation in wild-type mast cells, GAB2 becomes tyrosyl-phosphorylated and associates with Kit and Shp-2. Tyr567, an SFK binding site in Kit, and SFK activity were required for GAB2 tyrosyl phosphorylation and association with Shp-2. By re-expressing GAB2 or a GAB2 mutant that cannot bind Shp-2 in GAB2–/– mast cells or acutely by deleting Shp-2 in mast cells, we found that GAB2 requires Shp-2 for SCF-evoked Rac/JNK, Ras activation, and mast cell proliferation. Lastly, by analyzing mast cells from mice with compound GAB2 and Kit Y719F mutations (i.e., GAB2–/–: KitY719F/Y719F mice), we find that GAB2, acting in a parallel pathway to PI3K from Kit Tyr719, regulates mast cell proliferation and development in specific tissues. Our data show that GAB2 via Shp-2 is critical for transmitting signals from Kit Tyr567 to activate the Rac/JNK pathway controlling mast cell proliferation, which likely contributes to mast cell development in specific tissues.
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A role for the scaffolding adapter GAB2 in breast cancer
Nature medicine, 2005Co-Authors: Mohamed Bentires-alj, Yongping Wang, Susana G Gil, Richard Chan, Zhigang C. Wang, Naoko Imanaka, Lyndsay Harris, Andrea L. Richardson, Benjamin G NeelAbstract:The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of GAB2 potentiates, whereas deficiency of GAB2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.
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Critical role for scaffolding adapter GAB2 in FcγR-mediated phagocytosis
The Journal of cell biology, 2003Co-Authors: Roberto J. Botelho, Sergio Grinstein, Benjamin G NeelAbstract:Grb2-associated binder 2 (GAB2), a member of the Dos/Gab subfamily scaffolding molecules, plays important roles in regulating the growth, differentiation, and function of many hematopoietic cell types. In this paper, we reveal a novel function of GAB2 in Fcγ receptor (FcγR)–initiated phagocytosis in macrophages. Upon FcγR activation, GAB2 becomes tyrosyl phosphorylated and associated with p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and the protein–tyrosine phosphatidylinositol Shp-2. FcγR-mediated phagocytosis is severely impaired in bone marrow–derived macrophages from GAB2−/− mice. The defect in phagocytosis correlates with decreased FcγR-evoked activation of Akt, a downstream target of PI3K. Using confocal fluorescence microscopy, we find that GAB2 is recruited to the nascent phagosome, where de novo PI3K lipid production occurs. GAB2 recruitment requires the pleckstrin homology domain of GAB2 and is sensitive to treatment with the PI3K inhibitor wortmannin. The Grb2 binding site on GAB2 also plays an auxiliary role in recruitment to the phagosome. Because PI3K activity is required for FcγR-mediated phagocytosis, our results indicate that GAB2 acts as a key component of FcγR-mediated phagocytosis, most likely by amplifying PI3K signaling in the nascent phagosome.
Morag Park - One of the best experts on this subject based on the ideXlab platform.
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GAB2 requires membrane targeting and the Met binding motif to promote lamellipodia, cell scatter, and epithelial morphogenesis downstream from the Met receptor.
Journal of Cellular Physiology, 2007Co-Authors: Melanie M. Frigault, Monica A. Naujokas, Morag ParkAbstract:Gab1 and GAB2 are conserved scaffolding proteins that amplify and integrate signals stimulated by many growth factor receptors including the Met receptor. Gab1 acts to diversify the signal downstream from Met through the recruitment of multiple signaling proteins, and is essential for epithelial morphogenesis. However, whereas Gab1 and GAB2 are both expressed in epithelial cells, GAB2 fails to support a morphogenic response. We demonstrate that Gab1 and GAB2 are divergent in their function whereby Gab1, but not GAB2, promotes lamellipodia formation, and is localized to the membrane of lamellipodia upon Met activation. We have identified activation of ERK1/2 as a requirement for lamellipodia formation. Moreover, activated ERK1/2 are localized to lamellipodia in Gab1 expressing cells but not in cells that overexpress GAB2. By structure–function studies, we identify that enhanced membrane localization conferred through the addition of a myristoylation signal, together with the addition of the direct Met binding motif (MBM) from Gab1, are required to promote lamellipodia and confer a morphogenic signaling response to GAB2. Moreover, the morphogenesis competent myristoylated GAB2MBM promotes localization of activated ERK1/2 to the leading edge of lamellipodia in a similar manner to Gab1. Hence, subcellular localization of the Gab scaffold, as well as the ability of Gab to interact directly with the Met receptor, are both essential components of the morphogenic signaling response which involves lamellipodia formation and the localization of ERK1/2 activation in membrane ruffles. J. Cell. Physiol. 214: 694–705, 2008. © 2007 Wiley-Liss, Inc.
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Distinct Recruitment and Function of Gab1 and GAB2 in Met Receptor-mediated Epithelial Morphogenesis
Molecular biology of the cell, 2002Co-Authors: Lisa S Lock, Monica A. Naujokas, Christiane R. Maroun, Morag ParkAbstract:The Gab family of docking proteins (Gab1 and GAB2) are phosphorylated in response to various cytokines and growth factors. Gab1 acts to diversify the signal downstream from the Met receptor tyrosine kinase through the recruitment of multiple signaling proteins, and is essential for epithelial morphogenesis. To determine whether Gab1 and GAB2 are functionally redundant, we have examined the role of GAB2 in epithelial cells. Both Gab1 and GAB2 are expressed in epithelial cells and localize to cell-cell junctions. However, whereas overexpression of Gab1 promotes a morphogenic response, the overexpression of GAB2 fails to induce this response. We show that GAB2 recruitment to the Met receptor is dependent on the Grb2 adapter protein. In contrast, Gab1 recruitment to Met is both Grb2 dependent and Grb2 independent. The latter requires a novel amino acid sequence present in the Met-binding domain of Gab1 but not GAB2. Mutation of these residues in Gab1 impairs both association with the Met receptor and the ability of Gab1 to promote a morphogenic response, whereas their insertion into GAB2 increases GAB2 association with Met, but does not confer on GAB2 the ability to promote epithelial morphogenesis. We propose that the Grb2-independent recruitment of Gab proteins to Met is necessary but not sufficient to promote epithelial morphogenesis.
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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
Journal of Biological Chemistry, 2000Co-Authors: Lisa S Lock, Monica A. Naujokas, Isabelle Royal, Morag ParkAbstract:Abstract The Gab family of docking proteins is phosphorylated in response to various growth factors and cytokines and serves to recruit multiple signaling proteins. Gab1 acts downstream from the Met-hepatocyte growth factor receptor, and Gab1 overexpression promotes Met-dependent morphogenesis of epithelial cells. Recruitment of Gab1 to Met or epidermal growth factor (EGF) receptors requires a receptor-binding site for the Grb2 adapter protein and a proline-rich domain in Gab1, defined as the Met-binding domain. To determine the requirement for Grb2 in Gab1 recruitment, we have mapped two Grb2 carboxyl-terminal SH3 domain binding sites conserved in Gab1 and related protein GAB2. One corresponds to a canonical Grb2-binding motif, whereas the second, located within the Gab1 Met-binding domain, requires the proline and arginine residues of an atypical PXXXR motif. The PXXXR motif is required but not sufficient for Grb2 binding, whereas an extended motif, PX3RX2KPX7PLD, conserved in Gab proteins as well as the Grb2/Gads-docking protein, Slp-76, efficiently competes binding of Grb2 or Gads adapter proteins. The association of Gab1 with Grb2 is required for Gab1 recruitment to the EGF receptor but not the Met receptor. Hence different mechanisms of Gab1 recruitment may reflect the distinct biological functions for Gab1 downstream from the EGF and Met receptors.
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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.
The Journal of biological chemistry, 2000Co-Authors: Lisa S Lock, Monica A. Naujokas, Isabelle Royal, Morag ParkAbstract:Abstract The Gab family of docking proteins is phosphorylated in response to various growth factors and cytokines and serves to recruit multiple signaling proteins. Gab1 acts downstream from the Met-hepatocyte growth factor receptor, and Gab1 overexpression promotes Met-dependent morphogenesis of epithelial cells. Recruitment of Gab1 to Met or epidermal growth factor (EGF) receptors requires a receptor-binding site for the Grb2 adapter protein and a proline-rich domain in Gab1, defined as the Met-binding domain. To determine the requirement for Grb2 in Gab1 recruitment, we have mapped two Grb2 carboxyl-terminal SH3 domain binding sites conserved in Gab1 and related protein GAB2. One corresponds to a canonical Grb2-binding motif, whereas the second, located within the Gab1 Met-binding domain, requires the proline and arginine residues of an atypical PXXXR motif. The PXXXR motif is required but not sufficient for Grb2 binding, whereas an extended motif, PX3RX2KPX7PLD, conserved in Gab proteins as well as the Grb2/Gads-docking protein, Slp-76, efficiently competes binding of Grb2 or Gads adapter proteins. The association of Gab1 with Grb2 is required for Gab1 recruitment to the EGF receptor but not the Met receptor. Hence different mechanisms of Gab1 recruitment may reflect the distinct biological functions for Gab1 downstream from the EGF and Met receptors.
Isabelle Royal - One of the best experts on this subject based on the ideXlab platform.
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Non-redundant roles of the Gab1 and GAB2 scaffolding adapters in VEGF-mediated signalling, migration, and survival of endothelial cells.
Cellular signalling, 2009Co-Authors: Christine Caron, Kathleen Spring, Mélanie Laramée, Catherine Chabot, Monikca Cloutier, Isabelle RoyalAbstract:Abstract Gab1 was previously described as a positive modulator of Akt, Src, ERK1/2, endothelial cell migration, and capillary formation in response to vascular endothelial growth factor (VEGF). However, its involvement in endothelial cell survival, as well as the potential contribution of the other family member GAB2 to signalling and biological responses remained unknown. Here, we show that GAB2 is tyrosine phosphorylated in a Grb2-dependent manner downstream of activated VEGF receptor-2 (VEGFR2), and that it associates with signalling proteins including PI3K and SHP2, but apparently not with the receptor. Similarly to Gab1, over-expression of GAB2 induces endothelial cell migration in response to VEGF, whereas its depletion using siRNAs results in its reduction. Importantly, depletion of both Gab1 and GAB2 leads to an even greater inhibition of VEGF-induced cell migration. However, contrary to what has been reported for Gab1, the silencing of GAB2 results in increased Src, Akt and ERK1/2 activation, slightly reduced p38 phosphorylation, and up-regulation of Gab1 protein levels. Accordingly, re-expression of GAB2 in GAB2−/− fibroblasts leads to opposite results, suggesting that the modulation of both GAB2 and Gab1 expression in these conditions might contribute to the impaired signalling observed. Consistent with their opposite roles on Akt, the depletion of Gab1, but not of GAB2, results in reduced FOXO1 phosphorylation and VEGF-mediated endothelial cell survival. Mutation of VEGFR2 Y801 and Y1214, which abrogates the phosphorylation of Gab1, also correlates with inhibition of Akt. Altogether, these results underscore the non-redundant and essential roles of Gab1 and GAB2 in endothelial cells, and suggest major contributions of these proteins during in vivo angiogenesis.
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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
Journal of Biological Chemistry, 2000Co-Authors: Lisa S Lock, Monica A. Naujokas, Isabelle Royal, Morag ParkAbstract:Abstract The Gab family of docking proteins is phosphorylated in response to various growth factors and cytokines and serves to recruit multiple signaling proteins. Gab1 acts downstream from the Met-hepatocyte growth factor receptor, and Gab1 overexpression promotes Met-dependent morphogenesis of epithelial cells. Recruitment of Gab1 to Met or epidermal growth factor (EGF) receptors requires a receptor-binding site for the Grb2 adapter protein and a proline-rich domain in Gab1, defined as the Met-binding domain. To determine the requirement for Grb2 in Gab1 recruitment, we have mapped two Grb2 carboxyl-terminal SH3 domain binding sites conserved in Gab1 and related protein GAB2. One corresponds to a canonical Grb2-binding motif, whereas the second, located within the Gab1 Met-binding domain, requires the proline and arginine residues of an atypical PXXXR motif. The PXXXR motif is required but not sufficient for Grb2 binding, whereas an extended motif, PX3RX2KPX7PLD, conserved in Gab proteins as well as the Grb2/Gads-docking protein, Slp-76, efficiently competes binding of Grb2 or Gads adapter proteins. The association of Gab1 with Grb2 is required for Gab1 recruitment to the EGF receptor but not the Met receptor. Hence different mechanisms of Gab1 recruitment may reflect the distinct biological functions for Gab1 downstream from the EGF and Met receptors.
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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.
The Journal of biological chemistry, 2000Co-Authors: Lisa S Lock, Monica A. Naujokas, Isabelle Royal, Morag ParkAbstract:Abstract The Gab family of docking proteins is phosphorylated in response to various growth factors and cytokines and serves to recruit multiple signaling proteins. Gab1 acts downstream from the Met-hepatocyte growth factor receptor, and Gab1 overexpression promotes Met-dependent morphogenesis of epithelial cells. Recruitment of Gab1 to Met or epidermal growth factor (EGF) receptors requires a receptor-binding site for the Grb2 adapter protein and a proline-rich domain in Gab1, defined as the Met-binding domain. To determine the requirement for Grb2 in Gab1 recruitment, we have mapped two Grb2 carboxyl-terminal SH3 domain binding sites conserved in Gab1 and related protein GAB2. One corresponds to a canonical Grb2-binding motif, whereas the second, located within the Gab1 Met-binding domain, requires the proline and arginine residues of an atypical PXXXR motif. The PXXXR motif is required but not sufficient for Grb2 binding, whereas an extended motif, PX3RX2KPX7PLD, conserved in Gab proteins as well as the Grb2/Gads-docking protein, Slp-76, efficiently competes binding of Grb2 or Gads adapter proteins. The association of Gab1 with Grb2 is required for Gab1 recruitment to the EGF receptor but not the Met receptor. Hence different mechanisms of Gab1 recruitment may reflect the distinct biological functions for Gab1 downstream from the EGF and Met receptors.
Toshio Hirano - One of the best experts on this subject based on the ideXlab platform.
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the role of gab family scaffolding adapter proteins in the signal transduction of cytokine and growth factor receptors
Cancer Science, 2003Co-Authors: Keigo Nishida, Toshio HiranoAbstract:The Grb2-associated binder (Gab) family adapter proteins are scaffolding adapter molecules that display sequence similarity with Drosophila DOS (daughter of sevenless), which is a substrate for the protein tyrosine phosphatase Corkscrew. Gab proteins contain a pleckstrin homology (PH) domain and binding sites for SH2 and SH3 domains. A number of studies in multiple systems have implicated Gab in signaling via many different types of receptors, such as growth factor, cytokine, and antigen receptors, and via oncoproteins. Recent studies of Gab1 and GAB2 knockout mice have clearly indicated an important role for Gabs in vivo. Gab1-deficient mice die as embryos with multiple defects in placental, heart, skin, and muscle development. GAB2-deficient mice are viable, but have a defect in the mast cell lineages and in allergic reactions. Given the apparently central role played by Gab signaling via many receptors, delineating the precise mechanism(s) of Gab-mediated signaling is critical to understanding how cytokines, growth factors, and oncoproteins mediate a variety of biological activities: cell growth, differentiation, survival and malignant transformation.
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Gads/Grb2-mediated association with LAT is critical for the inhibitory function of GAB2 in T cells.
Molecular and cellular biology, 2003Co-Authors: Sho Yamasaki, Toshio Hirano, Keigo Nishida, Machie Sakuma, Donna M. Berry, C. Jane Mcglade, Takashi SaitoAbstract:A docking protein, GAB2, is recruited to the vicinity of the TCR complex and inhibits downstream signaling by interaction with negative regulators. However, the molecular mechanisms of this recruitment remain unclear. We have found that GAB2 associates with LAT upon TCR stimulation and that LAT is essential for GAB2 phosphorylation. By analysis of several GAB2 mutants, the c-Met binding domain (MBD) of GAB2 was found to be both necessary and sufficient for stimulation-induced LAT binding. Within the MBD domain, a novel Grb2 SH3 binding motif, PXXXR, is critical for constitutive association with Gads/Grb2. Through this association, GAB2 is recruited to the lipid raft after TCR ligation and exerts inhibitory function. The in vivo significance of this association is illustrated by the fact that T-cell responses are impaired in transgenic mice expressing wild-type GAB2 but not in mice expressing mutant GAB2 lacking the motif. Furthermore, T cells from GAB2-deficient mice showed enhanced proliferative responses upon TCR stimulation. These results indicate that Gads/Grb2-mediated LAT association is critical for the inhibitory function of GAB2, implying that GAB2 induced in stimulated T cells may exert an efficient negative feedback loop by recruiting inhibitory molecules to the lipid raft and competing with SLP-76 through Gads binding.
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gads grb2 mediated association with lat is critical for the inhibitory function of GAB2 in t cells
Molecular and Cellular Biology, 2003Co-Authors: Sho Yamasaki, Toshio Hirano, Keigo Nishida, Machie Sakuma, Donna M. Berry, Jane C Mcglade, Takashi SaitoAbstract:A docking protein, GAB2, is recruited to the vicinity of the TCR complex and inhibits downstream signaling by interaction with negative regulators. However, the molecular mechanisms of this recruitment remain unclear. We have found that GAB2 associates with LAT upon TCR stimulation and that LAT is essential for GAB2 phosphorylation. By analysis of several GAB2 mutants, the c-Met binding domain (MBD) of GAB2 was found to be both necessary and sufficient for stimulation-induced LAT binding. Within the MBD domain, a novel Grb2 SH3 binding motif, PXXXR, is critical for constitutive association with Gads/Grb2. Through this association, GAB2 is recruited to the lipid raft after TCR ligation and exerts inhibitory function. The in vivo significance of this association is illustrated by the fact that T-cell responses are impaired in transgenic mice expressing wild-type GAB2 but not in mice expressing mutant GAB2 lacking the motif. Furthermore, T cells from GAB2-deficient mice showed enhanced proliferative responses upon TCR stimulation. These results indicate that Gads/Grb2-mediated LAT association is critical for the inhibitory function of GAB2, implying that GAB2 induced in stimulated T cells may exert an efficient negative feedback loop by recruiting inhibitory molecules to the lipid raft and competing with SLP-76 through Gads binding.
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gab family adapter molecules in signal transduction of cytokine and growth factor receptors and t and b cell antigen receptors
Leukemia & Lymphoma, 2000Co-Authors: Masahiko Hibi, Toshio HiranoAbstract:Gab1 and GAB2 (Grb2 associated binder 1 and 2) are scaffolding adapter molecules that display sequence similarity with Drosophila DOS (daughter of sevenless), which is a potential substrate for the protein tyrosine phosphatase, Corkscrew. Both Gab1 and GAB2, like DOS, have a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains. Gab1 and GAB2 are phosphorylated on tyrosine upon the stimulation of various cytokines, growth factors, and antigen receptors, and interact with signaling molecules, such as Grb2, SHP-2, and PI-3 kinase. Overexpression of Gab1 or GAB2 mimics or enhances growth factor or cytokine-mediated biological processes and activates ERK MAP kinase. These data imply that Gab 1 and GAB2 act downstream of a broad range of cytokine and growth factor receptors, as well as T and B antigen receptors, and link these receptors to ERK MAP kinase and biological actions.
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gab family adapter molecules in signal transduction of cytokine and growth factor receptors and t and b cell antigen receptors
Leukemia & Lymphoma, 2000Co-Authors: Masahiko Hibi, Toshio HiranoAbstract:Gab1 and GAB2 (Grb2 associated binder 1 and 2) are scaffolding adapter molecules that display sequence similarity with Drosophila DOS (daughter of sevenless), which is a potential substrate for the protein tyrosine phosphatase, Corkscrew. Both Gab1 and GAB2, like DOS, have a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains. Gab1 and GAB2 are phosphorylated on tyrosine upon the stimulation of various cytokines, growth factors, and antigen receptors, and interact with signaling molecules, such as Grb2, SHP-2, and PI-3 kinase. Overexpression of Gab1 or GAB2 mimics or enhances growth factor or cytokine-mediated biological processes and activates ERK MAP kinase. These data imply that Gab 1 and GAB2 act downstream of a broad range of cytokine and growth factor receptors, as well as T and B antigen receptors, and link these receptors to ERK MAP kinase and biological actions.
Yongping Wang - One of the best experts on this subject based on the ideXlab platform.
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the scaffolding adapter GAB2 via shp 2 regulates kit evoked mast cell proliferation by activating the rac jnk pathway
Journal of Biological Chemistry, 2006Co-Authors: Jincai Luo, Yongping Wang, Wentian Yang, Masao Mizuki, Yuzuru Kanakura, Peter Besmer, Benjamin G NeelAbstract:Abstract The scaffolding adapter GAB2 mediates cell signaling and responses evoked by various extracellular stimuli including several growth factors. Kit, the receptor for stem cell factor (SCF), plays a critical role in the proliferation and differentiation of a variety of cell types, including mast cells. Kit, via Tyr567 and Tyr719, activates Src family kinases (SFK) and PI3K respectively, which converge on the activation of a Rac/JNK pathway required for mast cell proliferation. However, how Kit Tyr567 signals to Rac/JNK is not well understood. By analyzing GAB2–/– mast cells, we find that GAB2 is required for SCF-evoked proliferation, activation of Rac/JNK, and Ras. Upon Kit activation in wild-type mast cells, GAB2 becomes tyrosyl-phosphorylated and associates with Kit and Shp-2. Tyr567, an SFK binding site in Kit, and SFK activity were required for GAB2 tyrosyl phosphorylation and association with Shp-2. By re-expressing GAB2 or a GAB2 mutant that cannot bind Shp-2 in GAB2–/– mast cells or acutely by deleting Shp-2 in mast cells, we found that GAB2 requires Shp-2 for SCF-evoked Rac/JNK, Ras activation, and mast cell proliferation. Lastly, by analyzing mast cells from mice with compound GAB2 and Kit Y719F mutations (i.e., GAB2–/–: KitY719F/Y719F mice), we find that GAB2, acting in a parallel pathway to PI3K from Kit Tyr719, regulates mast cell proliferation and development in specific tissues. Our data show that GAB2 via Shp-2 is critical for transmitting signals from Kit Tyr567 to activate the Rac/JNK pathway controlling mast cell proliferation, which likely contributes to mast cell development in specific tissues.
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The Scaffolding Adapter GAB2, via Shp-2, Regulates Kit-evoked Mast Cell Proliferation by Activating the Rac/JNK Pathway
The Journal of biological chemistry, 2006Co-Authors: Jincai Luo, Yongping Wang, Wentian Yang, Masao Mizuki, Yuzuru Kanakura, Peter Besmer, Benjamin G NeelAbstract:Abstract The scaffolding adapter GAB2 mediates cell signaling and responses evoked by various extracellular stimuli including several growth factors. Kit, the receptor for stem cell factor (SCF), plays a critical role in the proliferation and differentiation of a variety of cell types, including mast cells. Kit, via Tyr567 and Tyr719, activates Src family kinases (SFK) and PI3K respectively, which converge on the activation of a Rac/JNK pathway required for mast cell proliferation. However, how Kit Tyr567 signals to Rac/JNK is not well understood. By analyzing GAB2–/– mast cells, we find that GAB2 is required for SCF-evoked proliferation, activation of Rac/JNK, and Ras. Upon Kit activation in wild-type mast cells, GAB2 becomes tyrosyl-phosphorylated and associates with Kit and Shp-2. Tyr567, an SFK binding site in Kit, and SFK activity were required for GAB2 tyrosyl phosphorylation and association with Shp-2. By re-expressing GAB2 or a GAB2 mutant that cannot bind Shp-2 in GAB2–/– mast cells or acutely by deleting Shp-2 in mast cells, we found that GAB2 requires Shp-2 for SCF-evoked Rac/JNK, Ras activation, and mast cell proliferation. Lastly, by analyzing mast cells from mice with compound GAB2 and Kit Y719F mutations (i.e., GAB2–/–: KitY719F/Y719F mice), we find that GAB2, acting in a parallel pathway to PI3K from Kit Tyr719, regulates mast cell proliferation and development in specific tissues. Our data show that GAB2 via Shp-2 is critical for transmitting signals from Kit Tyr567 to activate the Rac/JNK pathway controlling mast cell proliferation, which likely contributes to mast cell development in specific tissues.
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A role for the scaffolding adapter GAB2 in breast cancer
Nature medicine, 2005Co-Authors: Mohamed Bentires-alj, Yongping Wang, Susana G Gil, Richard Chan, Zhigang C. Wang, Naoko Imanaka, Lyndsay Harris, Andrea L. Richardson, Benjamin G NeelAbstract:The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of GAB2 potentiates, whereas deficiency of GAB2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.
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essential role for GAB2 in the allergic response
Nature, 2001Co-Authors: Haihua Gu, Lori D Klaman, Junqing Shen, Tony Fleming, Joanne C Pratt, Jean Pierre Kinet, Kan Saito, Yongping Wang, Benjamin G NeelAbstract:Dos/Gab family scaffolding adapters (Dos, Gab1, GAB2) bind several signal relay molecules, including the protein-tyrosine phosphatase Shp-2 and phosphatidylinositol-3-OH kinase (PI(3)K); they are also implicated in growth factor, cytokine and antigen receptor signal transduction1. Mice lacking Gab1 die during embryogenesis and show defective responses to several stimuli2,3. Here we report that GAB2-/- mice are viable and generally healthy; however, the response (for example, degranulation and cytokine gene expression) of GAB2-/- mast cells to stimulation of the high affinity immunoglobulin-e (IgE) receptor FceRI is defective. Accordingly, allergic reactions such as passive cutaneous and systemic anaphylaxis are markedly impaired in GAB2-/- mice. Biochemical analyses reveal that signalling pathways dependent on PI(3)K, a critical component of FceRI signalling, are defective in GAB2-/- mast cells. Our data identify GAB2 as the principal activator of PI(3)K in response to FceRI activation, thereby providing genetic evidence that Dos/Gab family scaffolds regulate the PI(3)K pathway in vivo. GAB2 and/or its associated signalling molecules may be new targets for developing drugs to treat allergy.
