The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor.

The SH2 domain-containing protein tyrosine phosphatase SHP-1 is expressed widely in the hematopoietic system. SHP-1 has been shown to negatively control signal transduction from many cytokine receptors by direct docking to either the receptor itself, or to members of the Jak family of tyrosine kinases which are themselves part of the receptor complex. Motheaten and viable motheaten mice, which are deficient in SHP-1, have increased myelopoiesis and show an accumulation of morphologically and phenotypically immature granulocytes, suggesting a role for SHP-1 in granulocytic differentiation. Here, we report that SHP-1 protein levels are up-regulated during the granulocyte colony-stimulating factor (G-CSF)-mediated granulocytic differentiation of myeloid 32D cells. Enforced expression of SHP-1 in these cells leads to decreased proliferation and enhanced differentiation, while introduction of a catalytically inactive mutant produces increased proliferation and results in a delay of differentiation. In vitro binding revealed that the SH2 domains of SHP-1 are unable to associate directly with tyrosine-phosphorylated G-CSF receptor (G-CSF-R). Furthermore, over-expression of SHP-1 in Ba/F3 cells expressing a G-CSF-R mutant lacking all cytoplasmic tyrosines also inhibited proliferation. Together, these data suggest that SHP-1 directly modulates G-CSF-mediated responses in hematopoietic cells via a mechanism that does not require docking to the activated G-CSF-R.