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Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo

Item Type:Article
Title:Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo
Creators Name:Schaeper, U. and Vogel, R. and Chmielowiec, J. and Huelsken, J. and Rosario, M. and Birchmeier, W.
Abstract:Gab1 is a multiadaptor protein that has been shown to be required for multiple processes in embryonic development and oncogenic transformation. Gab1 functions by amplifying signal transduction downstream of various receptor tyrosine kinases through recruitment of multiple signaling effectors, including phosphatidylinositol 3-kinase and Shp2. Until now, the functional significance of individual interactions in vivo was not known. Here we have generated knockin mice that carry point mutations in either the P13K or Shp2 binding sites of Gab1. We show that different effector interactions with Gab1 play distinct biological roles downstream of Gab1 during the development of different organs. Recruitment of phosphatidylinositol 3-kinase by Gab1 is essential for EGF receptor-mediated embryonic eyelid closure and keratinocyte migration, and the Gab1-Shp2 interaction is crucial for Met receptor-directed placental development and muscle progenitor cell migration to the limbs. Furthermore, we investigate the dual association of Gab1 with the Met receptor. By analyzing knockin mice with mutations in the Grb2 or Met binding site of Gab1, we show that the requirements for Gab1 recruitment to Met varies in different biological contexts. Either the direct or the indirect interaction of Gab1 with Met is sufficient for Met-dependent muscle precursor cell migration, whereas both modes of interaction are required and neither is sufficient for placenta development, liver growth, and palatal shelf closure. These data demonstrate that Gab1 induces different biological responses through the recruitment of distinct effectors and that different modes of recruitment for Gab1 are required in different organs.
Keywords:Developmental Pathways, Gab1 Docking Sites, Multiadaptor Protein, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences (U.S.A.)
Page Range:15376-15381
Date:25 September 2007
Additional Information:Copyright (c) 2007 by The National Academy of Sciences
Official Publication:https://doi.org/10.1073/pnas.0702555104
PubMed:View item in PubMed

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