Positive regulation of interleukin-4-mediated proliferation by the SH2-containing inositol-5 '-phosphatase

The SH2-containing inositol 5'-phosphatase (SHIP) is tyrosine-phosphorylate d in response to cytokines such as interleukin (LL)-3, granulocyte-macropha ge colony-stimulating factor, and macrophage colony-stimulating factor. SHI P has been shown to modulate negatively these cytokine signalings; however, a potential role in IL-4 signaling remains uncharacterized, It has been re cently shown that IL-4 induces tyrosine phosphorylation of SKIP, implicatin g the phosphatase in IL-4 processes. Tyrosine kinases, Jak1 and Jak3, invol ved in IL-4 signaling can associate with SHIP, yet only Jak1 can tyrosine-p hosphorylate SHIP when co-expressed. In functional studies, cells overexpre ssing wild type SHIP are found to be hyperproliferative in response to IL-4 in comparison to parental cells. In contrast, cells expressing catalytical ly inactive form, SHIP(D672A), show reduced proliferation in response to IL -4. These changes in IL-4-induced proliferation correlate with alterations in phosphatidylinositol 3,4,5-triphosphate levels. However, no differential activation of STAT6, Akt, IRS-2, or p70(S6k), in response to IL-4, was obs erved in these cells. These data suggest that the catalytic activity of SHI P acts in a novel manner to influence IL-4 signaling. In addition, these da ta support recent findings that suggest there are uncharacterized signaling pathways downstream of phosphatidylinositol 3,4,5-triphosphate.