title: SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice.
abstract: 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.
authors.affiliation: Department of Biomedical and Molecular Sciences, Division of Cancer Biology & Genetics, Queen's University, Kingston, Ontario, Canada.
authors.forename: Namit
authors.initials: N
authors.lastname: Sharma
authors.forename: Vijay
authors.initials: V
authors.lastname: Kumar
authors.forename: Stephanie
authors.initials: S
authors.lastname: Everingham
authors.forename: Raghuveer Singh
authors.initials: RS
authors.lastname: Mali
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Li-Fan
authors.initials: LF
authors.lastname: Zeng
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Karin
authors.initials: K
authors.lastname: Hartmann
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.forename: Andrew W B
authors.initials: AW
authors.lastname: Craig
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D020868:Gene Silencing; D006706:Homeostasis; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000201:enzymology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D017931:DNA Primers; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D019009:Proto-Oncogene Proteins c-kit; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse