SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice

Sharma, Namit and Kumar, Vijay and Everingham, Stephanie and Mali, Raghuveer Singh and Kapur, Reuben and Zeng, Li-Fan and Zhang, Zhong-Yin and Feng, Gen-Sheng and Hartmann, Karin and Roers, Axel and Craig, Andrew W. B.. (2012) SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice. Molecular and Cellular Biology, 32 (14). pp. 2653-2663.

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Official URL: https://edoc.unibas.ch/70805/

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Mast cells require KIT receptor tyrosine kinase signaling for development and survival. Here, we report that SH2 domain-containing phosphatase 2 (SHP2) signaling downstream of KIT is essential for mast cell survival and homeostasis in mice. Using a novel mouse model with shp2 deletion within mature mast cells (MC-shp2 knockout [KO]), we find that SHP2 is required for the homeostasis of connective tissue mast cells. Consistently with the loss of skin mast cells, MC-shp2 KO mice fail to mount a passive late-phase cutaneous anaphylaxis response. To better define the phenotype of shp2-deficient mast cells, we used an inducible shp2 knockout approach in bone marrow-derived mast cells (BMMCs) or cultured peritoneal mast cells and found that SHP2 promotes mast cell survival. We show that SHP2 promotes KIT signaling to extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase and downregulation of the proapoptotic protein Bim in BMMCs. Also, SHP2-deficient BMMCs failed to repopulate mast cells in mast cell-deficient mice. Silencing of Bim partially rescued survival defects in shp2-deficient BMMCs, consistent with the importance of a KIT → SHP2 → Ras/ERK pathway in suppressing Bim and promoting mast cell survival. Thus, SHP2 is a key node in a mast cell survival pathway and a new potential therapeutic target in diseases involving mast cells.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Allergy and Immunity (Hartmann)
UniBasel Contributors:Hartmann, Karin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Nov 2020 17:03
Deposited On:10 Nov 2020 17:03

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