Integrin-mediated Tyrosine Phosphorylation of SHPS-1 and Its Association with SHP-2

• DOI: 10.1074/jbc.273.21.13223
• Publication Date: 2002-07-26T14:47:21Z
• Authors: Masahiro Tsuda; Takashi Matozaki; Kaoru Fukunaga; Yohsuke Fujioka; Akira Imamoto; Tetsuya Noguchi; Toshiyuki Takada; Takuji Yamao; Hitoshi Takeda; Fukashi Ochi; Tadashi Yamamoto; Masato Kasuga
• Keywords: Mice, Knockout; Integrins; 0303 health sciences; Membrane Glycoproteins; Intracellular Signaling Peptides and Proteins; Neural Cell Adhesion Molecule L1; Antigens, Differentiation; Catalysis; Cell Line; Fibronectins; Enzyme Activation; Mice; 03 medical and health sciences; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Calcium-Calmodulin-Dependent Protein Kinases; Animals; Laminin; Phosphorylation; Cell Adhesion Molecules; Neural Cell Adhesion Molecules; Protein Binding

SHPS-1 is a receptor-like glycoprotein that undergoes tyrosine phosphorylation and binds SHP-2, an Src homology 2 domain containing protein tyrosine phosphatase, in response to various mitogens. Cell adhesion to extracellular matrix proteins such as fibronectin and laminin also induced the tyrosine phosphorylation of SHPS-1 and its association with SHP-2. These responses were markedly reduced in cells overexpressing the Csk kinase or in cells that lack focal adhesion kinase or the Src family kinases Src or Fyn. However, unlike Src, focal adhesion kinase did not catalyze phosphorylation of the cytoplasmic domain of SHPS-1 in vitro. Overexpression of a catalytically inactive SHP-2 markedly inhibited activation of mitogen-activated protein (MAP) kinase in response to fibronectin stimulation without affecting the extent of tyrosine phosphorylation of focal adhesion kinase or its interaction with the docking protein Grb2. Overexpression of wild-type SHPS-1 did not enhance fibronectin-induced activation of MAP kinase. These results indicate that the binding of integrins to the extracellular matrix induces tyrosine phosphorylation of SHPS-1 and its association with SHP-2, and that such phosphorylation of SHPS-1 requires both focal adhesion kinase and an Src family kinase. In addition to its role in receptor tyrosine kinase-mediated MAP kinase activation, SHP-2 may play an important role, partly through its interaction with SHPS-1, in the activation of MAP kinase in response to the engagement of integrins by the extracellular matrix.