Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase

Mol Cell Biol. 1998 Jul;18(7):4109-17. doi: 10.1128/MCB.18.7.4109.

Abstract

Gab1 has structural similarities with Drosophila DOS (daughter of sevenless), which is a substrate of the protein tyrosine phosphatase Corkscrew. Both Gab1 and DOS have a pleckstrin homology domain and tyrosine residues, potential binding sites for various SH2 domain-containing adapter molecules when they are phosphorylated. We found that Gab1 was tyrosine phosphorylated in response to various cytokines, such as interleukin-6 (IL-6), IL-3, alpha interferon (IFN-alpha), and IFN-gamma. Upon the stimulation of IL-6 or IL-3, Gab1 was found to form a complex with phosphatidylinositol (PI)-3 kinase and SHP-2, a homolog of Corkscrew. Mutational analysis of gp130, the common subunit of IL-6 family cytokine receptors, revealed that neither tyrosine residues of gp130 nor its carboxy terminus was required for tyrosine phosphorylation of Gab1. Expression of Gab1 enhanced gp130-dependent mitogen-activated protein (MAP) kinase ERK2 activation. A mutation of tyrosine 759, the SHP-2 binding site of gp130, abrogated the interactions of Gab1 with SHP-2 and PI-3 kinase as well as ERK2 activation. Furthermore, ERK2 activation was inhibited by a dominant negative p85 PI-3 kinase, wortmannin, or a dominant negative Ras. These observations suggest that Gab1 acts as an adapter molecule in transmitting signals to ERK MAP kinase for the cytokine receptor gp130 and that SHP-2, PI-3 kinase, and Ras are involved in Gab1-mediated ERK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Cytokine Receptor gp130
  • Enzyme Activation
  • Humans
  • Interleukin-6 / metabolism
  • Interleukin-6 / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / metabolism*
  • Mitogen-Activated Protein Kinase 1
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Signal Transduction*
  • Tumor Cells, Cultured
  • Tyrosine / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • GAB1 protein, human
  • IL6ST protein, human
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Phosphoproteins
  • Cytokine Receptor gp130
  • Tyrosine
  • Phosphatidylinositol 3-Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • PTPN11 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • SH2 Domain-Containing Protein Tyrosine Phosphatases