title: Kit-Shp2-Kit signaling acts to maintain a functional hematopoietic stem and progenitor cell pool.
abstract: The stem cell factor (SCF)/Kit system has served as a classic model in deciphering molecular signaling events in the hematopoietic compartment, and Kit expression is a most critical marker for hematopoietic stem cells (HSCs) and progenitors. However, it remains to be elucidated how Kit expression is regulated in HSCs. Herein we report that a cytoplasmic tyrosine phosphatase Shp2, acting downstream of Kit and other RTKs, promotes Kit gene expression, constituting a Kit-Shp2-Kit signaling axis. Inducible ablation of PTPN11/Shp2 resulted in severe cytopenia in BM, spleen, and peripheral blood in mice. Shp2 removal suppressed the functional pool of HSCs/progenitors, and Shp2-deficient HSCs failed to reconstitute lethally irradiated recipients because of defects in homing, self-renewal, and survival. We show that Shp2 regulates coordinately multiple signals involving up-regulation of Kit expression via Gata2. Therefore, this study reveals a critical role of Shp2 in maintenance of a functional HSC/progenitor pool in adult mammals, at least in part through a kinase-phosphatase-kinase cascade.
authors: Department of Pathology, School of Medicine, and Section of Molecular Biology, Division of Biological Sciences, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Helen He
authors: HH
authors: Zhu
authors: Kaihong
authors: K
authors: Ji
authors: Nazilla
authors: N
authors: Alderson
authors: Zhao
authors: Z
authors: He
authors: Shuangwei
authors: S
authors: Li
authors: Wen
authors: W
authors: Liu
authors: Dong-Er
authors: DE
authors: Zhang
authors: Linheng
authors: L
authors: Li
authors: Gen-Sheng
authors: GS
authors: Feng
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000741:Anemia, Aplastic; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D025461:Feedback, Physiological; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000209:etiology; D007970:Leukopenia / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D034741:RNA, Small Interfering; D019009:Proto-Oncogene Proteins c-kit; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse