Regulation of colony-stimulating factor 1 receptor signaling by the SH2 domain-containing tyrosine phosphatase SHPTP1

Mol Cell Biol. 1996 Jul;16(7):3685-97. doi: 10.1128/mcb.16.7.3685.

Abstract

SHPTP1 (PTP1C, HCP, SHP) is an SH2 domain-containing tyrosine phosphatase expressed predominantly in hematopoietic cells. A frameshift mutation in the SHPTP1 gene causes the motheaten (me/me) mouse. These mice are essentially SHPTP1 null and display multiple hematopoietic abnormalities, most prominently hyperproliferation and inappropriate activation of granulocytes and macrophages. The me/me phenotype suggests that SHPTP1 negatively regulates macrophage proliferative pathways. Using primary bone marrow-derived macrophages from me/me mice and normal littermates, we examined the role of SHPTP1 in regulating signaling by the major macrophage mitogen colony-stimulating factor 1 (CSF-1) (also known as macrophage colony-stimulating factor). Macrophages from me/me mice hyperproliferate in response to CSF-1. In the absence of SHPTP1, the CSF-1 receptor (CSF-1R) is hyperphosphorylated upon CSF-1 stimulation, suggesting that SHPTP1 dephosphorylates the CSF-1R. At least some CSF-1R-associated proteins also are hyperactivated. SHPTP1 is associated constitutively, via its SH2 domains, with an unidentified 130-kDa phosphotyrosyl protein (P130). P130 and SHPTP1 are further tyrosyl phosphorylated upon CSF-1 stimulation. Tyrosyl-phosphorylated SHPTP1 binds to Grb2 via the Grb2 SH2 domain. Moreover, in me/me macrophages, Grb2 is associated, via its SH3 domains, with several tyrosyl phosphoproteins. These proteins are hyperphosphorylated on tyrosyl residues in me/me macrophages, suggesting that Grb2 may recruit substrates for SHPTP1. Our results indicate that SHPTP1 is a critical negative regulator of CSF-1 signaling in vivo and suggest a potential new function for Grb2.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Cells
  • Cell Division / drug effects
  • Cells, Cultured
  • Frameshift Mutation
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / physiology
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Macrophage Activation
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Macrophages / cytology*
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / isolation & purification
  • Protein Tyrosine Phosphatases / metabolism*
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Receptor, Macrophage Colony-Stimulating Factor / physiology*
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Signal Transduction
  • src Homology Domains

Substances

  • Intracellular Signaling Peptides and Proteins
  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse
  • SH2 Domain-Containing Protein Tyrosine Phosphatases