Tumor Suppression by Phospholipase C-β3 via SHP-1-Mediated Dephosphorylation of Stat5

Given its catalytic activity to generate diacylglycerol and inositol 1,4,5-trisphosphate, phospholipase C (PLC) is implicated in promoting cell growth. However, we found that PLC-beta 3-deficient mice develop myeloproliferative disease, lymphoma, and other tumors. The mutant mice have increased numbers of hematopoietic stem cells with increased proliferative, survival, and myeloid-differentiative abilities. These properties are dependent on Stat5 and can be antagonized by the protein phosphatase SHP-1. Stat5-dependent cooperative transformation by activec-Myc and PLC-beta 3 deficiency was suggested in mouse lymphomas in PLC-beta 3(-/-) and in E mu-myc;PLC-beta 3(+/-) mice and human Burkitt's lymphoma cells. The same mechanism for malignant transformation seems to be operative in other human lymphoid and myeloid malignancies. Thus, PLC-beta 3 is likely a tumor suppressor.