The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced bygranulocyte colony-stimulating factor (G-CSF) and modulates signaling fromthe G-CSF receptor

The SH2 domain-containing protein tyrosine phosphatase SHP-1 is expressed w idely in the hematopoietic system. SHP-1 has been shown to negatively contr ol signal transduction from many cytokine receptors by direct docking to ei ther the receptor itself, or to members of the Jak family of tyrosine kinas es which are themselves part of the receptor complex. Motheaten and viable motheaten mice, which are deficient in SHP-1, have increased myelopoiesis a nd show an accumulation of morphologically and phenotypically immature gran ulocytes, suggesting a role for SHP-1 in granulocytic differentiation. Here , we report that SHP-1 protein levels are up-regulated during the granulocy te 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 resul ts in a delay of differentiation. In vitro binding revealed that the SH2 do mains of SHP-1 are unable to associate directly with tyrosine-phosphorylate d 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 in hibited proliferation. Together, these data suggest that SHP-1 directly mod ulates G-CSF-mediated responses in hematopoietic cells via a mechanism that does not require docking to the activated G-CSF-R.