Regulation of early events in integrin signaling by protein tyrosine phosphatase SHP-2

Mol Cell Biol. 1999 Apr;19(4):3205-15. doi: 10.1128/mcb.19.4.3205.

Abstract

The nontransmembrane protein tyrosine phosphatase SHP-2 plays a critical role in growth factor and cytokine signaling pathways. Previous studies revealed that a fraction of SHP-2 moves to focal contacts upon integrin engagement and that SHP-2 binds to SHP substrate 1 (SHPS-1)/SIRP-1alpha, a transmembrane glycoprotein with adhesion molecule characteristics (Y. Fujioka et al., Mol. Cell. Biol. 16:6887-6899, 1996; M. Tsuda et al., J. Biol. Chem. 273:13223-13229). Therefore, we asked whether SHP2-SHPS-1 complexes participate in integrin signaling. SHPS-1 tyrosyl phosphorylation increased upon plating of murine fibroblasts onto specific extracellular matrices. Both in vitro and in vivo studies indicate that SHPS-1 tyrosyl phosphorylation is catalyzed by Src family protein tyrosine kinases (PTKs). Overexpression of SHPS-1 in 293 cells potentiated integrin-induced mitogen-activated protein kinase (MAPK) activation, and potentiation required functional SHP-2. To further explore the role of SHP-2 in integrin signaling, we analyzed the responses of SHP-2 exon 3(-/-) and wild-type cell lines to being plated on fibronectin. Integrin-induced activation of Src family PTKs, tyrosyl phosphorylation of several focal adhesion proteins, MAPK activation, and the ability to spread on fibronectin were defective in SHP-2 mutant fibroblasts but were restored upon SHP-2 expression. Our data suggest a positive-feedback model in which, upon integrin engagement, basal levels of c-Src activity catalyze the tyrosyl phosphorylation of SHPS-1, thereby recruiting SHP-2 to the plasma membrane, where, perhaps by further activating Src PTKs, SHP-2 transduces positive signals for downstream events such as MAPK activation and cell shape changes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Differentiation*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Adhesion Molecules / metabolism
  • Enzyme Activation
  • Fibroblasts / cytology
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Integrins / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Models, Biological
  • Neural Cell Adhesion Molecule L1*
  • Neural Cell Adhesion Molecules / metabolism*
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Immunologic*
  • Signal Transduction
  • Time Factors
  • Tyrosine / metabolism
  • src-Family Kinases / metabolism

Substances

  • Antigens, Differentiation
  • Cell Adhesion Molecules
  • Integrins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Neural Cell Adhesion Molecule L1
  • Neural Cell Adhesion Molecules
  • Ptpns1 protein, mouse
  • Receptors, Immunologic
  • Tyrosine
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Ptk2 protein, mouse
  • src-Family Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse