PRL2/PTP4A2 Phosphatase Is Important for Hematopoietic Stem Cell Self-Renewal

Authors

  • Michihiro Kobayashi,

    1. Department of Pediatrics, Herman B Wells Center for Pediatric Research and Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Yunpeng Bai,

    1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Yuanshu Dong,

    1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Hao Yu,

    1. Department of Pediatrics, Herman B Wells Center for Pediatric Research and Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Sisi Chen,

    1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Rui Gao,

    1. Department of Pediatrics, Herman B Wells Center for Pediatric Research and Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Lujuan Zhang,

    1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Mervin C. Yoder,

    1. Department of Pediatrics, Herman B Wells Center for Pediatric Research and Indiana University School of Medicine, Indianapolis, Indiana, USA
    2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Reuben Kapur,

    1. Department of Pediatrics, Herman B Wells Center for Pediatric Research and Indiana University School of Medicine, Indianapolis, Indiana, USA
    2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Search for more papers by this author
  • Zhong-Yin Zhang,

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    • Correspondence: Zhong-Yin Zhang, Ph.D., Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. e-mail: zyzhang@iu.edu; or Yan Liu, Ph.D., Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. e-mail: liu219@iu.edu

    Search for more papers by this author
  • Yan Liu

    Corresponding author
    1. Department of Pediatrics, Herman B Wells Center for Pediatric Research and Indiana University School of Medicine, Indianapolis, Indiana, USA
    2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    • Correspondence: Zhong-Yin Zhang, Ph.D., Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. e-mail: zyzhang@iu.edu; or Yan Liu, Ph.D., Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. e-mail: liu219@iu.edu

    Search for more papers by this author

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. Stem Cells 2014;32:1956–1967

Ancillary