Role of Gab1 in Heart, Placenta, and Skin Development and Growth Factor- and Cytokine-Induced Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Activation

ABSTRACT Gab1 is a member of the Gab/DOS (Daughter of Sevenless) family of adapter molecules, which contain a pleckstrin homology (PH) domain and potential binding sites for SH2 and SH3 domains. Gab1 is tyrosine phosphorylated upon stimulation of various cytokines, growth factors, and antigen receptors in cell lines and interacts with signaling molecules, such as SHP-2 and phosphatidylinositol 3-kinase, although its biological roles have not yet been established. To reveal the functions of Gab1 in vivo, we generated mice lacking Gab1 by gene targeting. Gab1-deficient embryos died in utero and displayed developmental defects in the heart, placenta, and skin, which were similar to phenotypes observed in mice lacking signals of the hepatocyte growth factor/scatter factor, platelet-derived growth factor, and epidermal growth factor pathways. Consistent with these observations, extracellular signal-regulated kinase mitogen-activated protein (ERK MAP) kinases were activated at much lower levels in cells from Gab1-deficient embryos in response to these growth factors or to stimulation of the cytokine receptor gp130. These results indicate that Gab1 is a common player in a broad range of growth factor and cytokine signaling pathways linking ERK MAP kinase activation.

[1]  Arun Sharma,et al.  Engagement of Gab1 and Gab2 in Erythropoietin Signaling* , 1999, The Journal of Biological Chemistry.

[2]  N. Asai,et al.  Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation. , 1999, Biochemical and biophysical research communications.

[3]  C. Betsholtz,et al.  PDGFB regulates the development of the labyrinthine layer of the mouse fetal placenta. , 1999, Developmental biology.

[4]  G. Feng,et al.  Gab2, a New Pleckstrin Homology Domain-containing Adapter Protein, Acts to Uncouple Signaling from ERK Kinase to Elk-1* , 1999, The Journal of Biological Chemistry.

[5]  C. Betsholtz,et al.  Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle. , 1999, Development.

[6]  T. Hirano,et al.  Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors. , 1999, Blood.

[7]  Tony Pawson,et al.  Mammalian Grb2 Regulates Multiple Steps in Embryonic Development and Malignant Transformation , 1998, Cell.

[8]  J. C. Pratt,et al.  Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation. , 1998, Molecular cell.

[9]  Keigo Nishida,et al.  Gab1 Acts as an Adapter Molecule Linking the Cytokine Receptor gp130 to ERK Mitogen-Activated Protein Kinase , 1998, Molecular and Cellular Biology.

[10]  Zhong-Qing Shi,et al.  The Shp-2 Tyrosine Phosphatase Has Opposite Effects in Mediating the Activation of Extracellular Signal-regulated and c-Jun NH2-terminal Mitogen-activated Protein Kinases* , 1998, The Journal of Biological Chemistry.

[11]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[12]  T. Hirano,et al.  Signaling mechanisms through gp130: a model of the cytokine system. , 1997, Cytokine & growth factor reviews.

[13]  A. Ullrich,et al.  Signal characteristics of G protein‐transactivated EGF receptor , 1997, The EMBO journal.

[14]  A. Wong,et al.  Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  T. Pawson,et al.  Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp‐2 , 1997, The EMBO journal.

[16]  W. Birchmeier,et al.  Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis , 1996, Nature.

[17]  T. Hirano,et al.  Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. , 1996, Immunity.

[18]  A. Simeone,et al.  Uncoupling of Grb2 from the Met Receptor In Vivo Reveals Complex Roles in Muscle Development , 1996, Cell.

[19]  G. Johnson,et al.  Epidermal Growth Factor Induces Coupling of Protein-tyrosine Phosphatase 1D to GRB2 via the COOH-terminal SH3 Domain of GRB2* , 1996, The Journal of Biological Chemistry.

[20]  T. Hirano,et al.  A central role for Stat3 in IL‐6‐induced regulation of growth and differentiation in M1 leukemia cells. , 1996, The EMBO journal.

[21]  P. Carroll,et al.  Daughter of Sevenless Is a Substrate of the Phosphotyrosine Phosphatase Corkscrew and Functions during Sevenless Signaling , 1996, Cell.

[22]  E. Hafen,et al.  DOS, a Novel Pleckstrin Homology Domain–Containing Protein Required for Signal Transduction between Sevenless and Ras1 in Drosophila , 1996, Cell.

[23]  J. Ihle.  STATs: Signal Transducers and Activators of Transcription , 1996, Cell.

[24]  A. Godwin,et al.  A Grb2-associated docking protein in EGF- and insulin-receptor signalling , 1996, Nature.

[25]  Carmen Birchmeier,et al.  Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud , 1995, Nature.

[26]  K. Herrup,et al.  Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. , 1995, Science.

[27]  C. Ware,et al.  Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. , 1995, Development.

[28]  Tetsuo Noda,et al.  Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor , 1995, Nature.

[29]  M. Sharpe,et al.  Scatter factor/hepatocyte growth factor is essential for liver development , 1995, Nature.

[30]  C. Heldin,et al.  Dimerization of cell surface receptors in signal transduction , 1995, Cell.

[31]  Philippe Soriano,et al.  Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. , 1994, Genes & development.

[32]  B Swolin,et al.  Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. , 1994, Genes & development.

[33]  C. Walsh,et al.  Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[34]  J. Nichols,et al.  Dicistronic targeting constructs: reporters and modifiers of mammalian gene expression. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Jonathan A. Cooper,et al.  A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase , 1994, Molecular and cellular biology.

[36]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[37]  David C. Lee,et al.  TGFα deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice , 1993, Cell.

[38]  E. Nice,et al.  Mice with a null mutation of the TGFα gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation , 1993, Cell.

[39]  O. Smithies,et al.  TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. , 1993, Cell.

[40]  Sheila M. Thomas,et al.  Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases , 1992, Nature.

[41]  G. V. Vande Woude,et al.  Expression of c‐met proto‐oncogene in COS cells induces the signal transducing high‐affinity receptor for hepatocyte growth factor , 1992, FEBS letters.