Lysophosphatidic acid-induced association of SHP-2 with SHPS-1: roles of RHO, FAK, and a SRC family kinase

Oncogene. 1998 Jun 11;16(23):3019-27. doi: 10.1038/sj.onc.1201839.

Abstract

SHPS-1 is an approximately 120 kDa glycosylated receptor like protein that contains three immunoglobulin-like domains in its extracellular region as well as four potential tyrosine phosphorylation and SRC homology 2 (SH2) domain binding sites in its cytoplasmic region. Lysophosphatidic acid (LPA) stimulated the rapid tyrosine phosphorylation of SHPS-1 and its subsequent association with SHP-2, a protein tyrosine phosphatase containing SH2 domains in Rat-1 fibroblasts. LAP-induced tyrosine phosphorylation of SHPS-1 was inhibited by Clostridium botulinum C3 exoenzyme (which inactivates RHO) but not by pertussis toxin. The protein kinase C activator phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA) also stimulated tyrosine phosphorylation of SHPS-1; however, down-regulation of protein kinase C by prolonged exposure of cells to TPA did not affect LAP-induced tyrosine phosphorylation of SHPS-1. LPA-induced tyrosine phosphorylation of SHPS-1 was markedly reduced in either focal adhesion kinase (FAK)-deficient mouse cells or CHO cells overexpressing the tyrosine kinase CSK. Overexpression of a catalytically inactivate SHP-2 markedly inhibited MAP kinase activation in response to low concentrations of LPA in CHO cells, whereas overexpression of a wild-type SHPS-1 did enhance this effect of LPA. Furthermore, MAP kinase activation in response to a low concentration of LPA was inhibited by botulinum C3 exoenzyme. These results indicate that LPA-induced tyrosine phosphorylation of SHPS-1 and its association with SHP-2 may be mediated by a RHO-dependent pathway that includes FAK and a SRC family kinase. Thus, in addition to its role in receptor tyrosine kinase-mediated MAP kinase activation, the formation of a complex between SHPS-1 and SHP-2 may, in part, play an important role in the activation of MAP kinase in response to low concentrations of LPA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / pharmacology
  • Animals
  • Antigens, Differentiation*
  • Botulinum Toxins*
  • CHO Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Catalysis
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / physiology*
  • Cell Line
  • Cricetinae
  • Enzyme Activation
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • GTP-Binding Proteins / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysophospholipids / metabolism*
  • Lysophospholipids / pharmacology
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Neural Cell Adhesion Molecule L1*
  • Neural Cell Adhesion Molecules / metabolism*
  • Pertussis Toxin
  • Phosphorylation
  • Protein Kinase C / physiology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / physiology*
  • Rats
  • Receptors, Immunologic*
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Tyrosine / metabolism
  • Virulence Factors, Bordetella / pharmacology
  • rho GTP-Binding Proteins
  • src-Family Kinases / physiology*

Substances

  • Antigens, Differentiation
  • Cell Adhesion Molecules
  • Intracellular Signaling Peptides and Proteins
  • Lysophospholipids
  • Membrane Glycoproteins
  • Neural Cell Adhesion Molecule L1
  • Neural Cell Adhesion Molecules
  • Ptpns1 protein, mouse
  • Receptors, Immunologic
  • SIRPA protein, human
  • Sirpa protein, rat
  • Virulence Factors, Bordetella
  • Tyrosine
  • ADP Ribose Transferases
  • exoenzyme C3, Clostridium botulinum
  • Pertussis Toxin
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Ptk2 protein, mouse
  • Ptk2 protein, rat
  • src-Family Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • PTPN11 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn11 protein, rat
  • Ptpn6 protein, mouse
  • Ptpn6 protein, rat
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Botulinum Toxins
  • GTP-Binding Proteins
  • rho GTP-Binding Proteins