title: PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal.
abstract: Hematopoietic stem cell (HSC) self-renewal is tightly controlled by cytokines and other signals in the microenvironment. While stem cell factor (SCF) is an early acting cytokine that activates the receptor tyrosine kinase KIT and promotes HSC maintenance, how SCF/KIT signaling is regulated in HSCs is poorly understood. The protein tyrosine phosphatase 4A (PTP4A) family (aka PRL [phosphatase of regenerating liver] phosphatases), consisting of PTP4A1/PRL1, PTP4A2/PRL2, and PTP4A3/PRL3, represents an intriguing group of phosphatases implicated in cell proliferation and tumorigenesis. However, the role of PTP4A in hematopoiesis remains elusive. To define the role of PTP4A in hematopoiesis, we analyzed HSC behavior in Ptp4a2 (Prl2) deficient mice. We found that Ptp4a2 deficiency impairs HSC self-renewal as revealed by serial bone marrow transplantation assays. Moreover, we observed that Ptp4a2 null hematopoietic stem and progenitor cells (HSPCs) are more quiescent and show reduced activation of the AKT and ERK signaling. Importantly, we discovered that the ability of PTP4A2 to enhance HSPC proliferation and activation of AKT and ERK signaling depends on its phosphatase activity. Furthermore, we found that PTP4A2 is important for SCF-mediated HSPC proliferation and loss of Ptp4a2 decreased the ability of oncogenic KIT/D814V mutant in promoting hematopoietic progenitor cell proliferation. Thus, PTP4A2 plays critical roles in regulating HSC self-renewal and mediating SCF/KIT signaling.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research and Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Bai
authors.forename: Yuanshu
authors.initials: Y
authors.lastname: Dong
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Sisi
authors.initials: S
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.forename: Lujuan
authors.initials: L
authors.lastname: Zhang
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000502:physiology
chemical_list: D017874:Immediate-Early Proteins; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D017027:Protein Tyrosine Phosphatases; C111533:Ptp4a2 protein, mouse
keywords: Cytokine signaling; Hematopoietic stem cell; KIT; KIT/D814V; PRL2; PTP4A2; Self-renewal; Stem cell factor
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