SHP2 protein-tyrosine phosphatase is a key regulator of mast cell signaling and development in mice (36.22)

Abstract

Abstract SH2 domain-containing phosphatase-2 (SHP2; also called PTPN11) is a positive effector of growth signaling pathways downstream of receptor tyrosine kinases and immune receptors. The development of conditional knockout mouse models for SHP2 has resulted in a better understanding of the role of SHP2 in adult tissues and cell types. In bone marrow-derived mast cells, recent studies have implicated SHP2 in functioning as a positive effector of growth signaling via Kit receptor tyrosine kinase, and TNFα production via the high affinity IgE receptor. In this study, we describe the use of transgenic mice expressing Cre recombinase in connective tissue mast cells (CTMCs) to generate a selective SHP2 knockout in CTMCs (MC-SHP2 KO). Compared to control mice lacking Cre, MC-SHP2 KO mice display a drastic reduction in mast cells within the peritoneum and skin. Previous studies have demonstrated the critical importance of Kit Y567 and Y719 signaling to Src family kinases/Gab2 and phosphatidylinositol 3’ kinase (PI3K) pathways for development of peritoneal and skin mast cells in mice. Thus, our results suggest that SHP2 plays a key role in signaling via the Src/Gab2/PI3K axis downstream of Kit during mast cell development in mice. In vitro differentiation assays for CTMCs are being investigated to further explore the molecular mechanisms by which SHP2 regulates mast cell development.