SH2 Domain-Containing Phosphatase 2 Is a Critical Regulator of Connective Tissue Mast Cell Survival and Homeostasis in Mice

Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in mice

“…In spi-1 transgenic mice, leukemic proerythroblasts with KIT D814Y (or D818Y) signal via SHP2 to enhance cell survival in vitro and tumor growth in vivo [28, 29]. In both erythroblast and mast cell leukemia cell lines, SHP2 silencing led to reduced Ras/MEK/ERK pathway activation, upregulation of Bim, and apoptosis [28, 29], which was consistent with our results in SHP2 knock-out (KO) mast cells [22]. In a KIT D814V -driven MPD model, SHP2 KO impaired transformation of bone marrow progenitors, and a small molecule inhibitor of SHP2 (II-B08) [30] was shown to synergize with a PI3K inhibitor to repress mast cell leukemia in MPD mice [31].…”

“…1A). Defects in ERK activation in a variety SHP2-deficient cell models leads to reductions in phosphorylation and proteosomal degradation of the proapoptotic Bim protein [22, 25, 29]. In P815-KD cells, we also observed reduced Bim phosphorylation and increased Bim EL levels compared to NT control (Fig.…”

“…Since SHP2 promotes survival signaling from wild-type and oncogenic KIT [22, 25, 29], we tested for effects of SHP2 silencing on KIT-dependent survival of P815 cells using Annexin V staining and flow cytometry. There was a small but significant increase in apoptotic P815-KD cells compared to P815-NT cells with vehicle alone (DMSO), and a more substantial increase following treatment with a low dose (250 nM) of KIT inhibitor SU11652 for 18 hours (Fig.…”

“…Several previous studies have implicated SHP2 in promoting wild-type KIT signaling to the Ras/ERK pathway leading to enhanced proliferation and survival of mature MCs [22, 27]. SHP2 also promotes activation of Lyn kinase and Stat5 pathways [31, 32], that are implicated in mechanisms to escape KIT inhibitor treatments [38].…”

“…In mast cells, SCF-induced KIT activation leads to recruitment of SHP2 to the juxtamembrane domain of KIT via the adaptor protein Gab2 [27]. In bone marrow-derived mast cells, SHP2 promotes KIT signaling to cell survival and proliferation pathways [22, 27]. Recent studies have also implicated SHP2 in playing a key role in oncogenic KIT signaling in a variety of cell types.…”