REGULATION OF COLONY-STIMULATING FACTOR-1 RECEPTOR SIGNALING BY THE SH2 DOMAIN-CONTAINING TYROSINE PHOSPHATASE SHPTP1

SHPTP1 (PTP1C, HCP, SHP) is an SH2 domain-containing tyrosine phosphat ase expressed predominantly in hematopoietic cells. A frameshift mutat ion in the SHPTP1 gene causes the motheaten (me/me) mouse. These mice are essentially SHPTP1 null and display multiple hematopoietic abnorma lities, most prominently hyperproliferation and inappropriate activati on of granulocytes and macrophages. The me/me phenotype suggests that SHPTP1 negatively regulates macrophage proliferative pathways. Using p rimary bone marrow-derived macrophages from me/me mice and normal litt ermates, we examined the role of SHPTP1 in regulating signaling by the major macrophage mitogen colony-stimulating factor 1 (CSF-1) (also kn own as macrophage colony-stimulating factor). Macrophages from me/me m ice hyperproliferate in response to CSF-1. In the absence of SHPTP1, t he CSF-1 receptor (CSF-1R) is hyperphosphorylated upon CSF-1 stimulati on, suggesting that SHPTP1 dephosphorylates the CSF-1R At least some C SF-1R-associated proteins also are hyperactivated. SHPTP1 is associate d constitutively, via its SH2 domains, with an unidentified 130-kDa ph osphotyrosyl protein (P130). P130 and SHPTP1 are further tyrosyl phosp horylated upon CSF-1 stimulation. Tyrosylphosphorylated SHPTP1 binds t o Grb2 via the Grb2 SH2 domain. Moreover, in me/me macrophages, Grb2 i s associated, via its SH3 domains, with several tyrosyl phosphoprotein s. 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 C SF-1 signaling in vivo and suggest a potential new function for Grb2.