The protein tyrosine phosphatase SHP-2 negatively regulates ciliary neurotrophic factor induction of gene expression

Curr Biol. 1997 Sep 1;7(9):697-700. doi: 10.1016/s0960-9822(06)00298-3.

Abstract

Ciliary neurotrophic factor, along with other neuropoietic cytokines, signals through the shared receptor subunit gp130 [1-3], leading to the tyrosine phosphorylation of a number of substrates [4,5], including the transcription factors STAT1 and STAT3 and the protein tyrosine phosphatase SHP-2 [6,7] [8]. SHP-2 (also known as PTP1D, SHPTP2, Syp and PTP2C) is a positive regulatory molecule required for the activation of the mitogen-activated protein kinase pathway and the stimulation of gene expression in response to epidermal growth factor, insulin and platelet-derived growth factor stimulation [9-11]. We have previously shown that cytokines that signal via the gp130 receptor subunit activate transcription of the vasoactive intestinal peptide (VIP) gene through a 180 bp cytokine response element (CyRE) [12,13]. To characterize the role of SHP-2 in the regulation of gp130-stimulated gene expression, we examined the regulation of the VIP CyRE in two systems that prevented ligand-dependent SHP-2 phosphorylation. Inhibition of SHP-2, either by mutating the tyrosine residue in gp130 that mediates the SHP-2 interaction, or by expression of dominant-negative SHP-2, resulted in dramatic increases in gp130-dependent gene expression, through the VIP CyRE and more specifically through multimerized STAT-binding sites. These data suggest that SHP-2 has a negative role in gp130 signaling by modulating STAT-mediated transcriptional activation.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Cell Line
  • Ciliary Neurotrophic Factor
  • Cytokine Receptor gp130
  • DNA-Binding Proteins / metabolism
  • Down-Regulation*
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / metabolism
  • Nerve Growth Factors / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism*
  • Regulatory Sequences, Nucleic Acid
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction
  • Trans-Activators / metabolism
  • Transcriptional Activation
  • Vasoactive Intestinal Peptide / genetics

Substances

  • Antigens, CD
  • Ciliary Neurotrophic Factor
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Trans-Activators
  • Cytokine Receptor gp130
  • Vasoactive Intestinal Peptide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases