PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal

Michihiro Kobayashi, Yunpeng Bai, Yuanshu Dong, Hao Yu, Sisi Chen, Rui Gao, Lujuan Zhang, Mervin Yoder, Reuben Kapur, Zhong-Yin Zhang, Yan Liu

Research output: Contribution to journalArticle

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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

Original languageEnglish
Pages (from-to)1956-1967
Number of pages12
JournalStem Cells
Volume32
Issue number7
DOIs
StatePublished - 2014

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Hematopoietic Stem Cells
Phosphoric Monoester Hydrolases
Stem Cell Factor
Protein Tyrosine Phosphatases
Cell Proliferation
Aptitude
Hematopoiesis
Cell Self Renewal
Cytokine Receptors
Bone Marrow Transplantation
Protein-Tyrosine Kinases
Carcinogenesis
Stem Cells
Maintenance
Cytokines

Keywords

  • Cytokine signaling
  • Hematopoietic stem cell
  • KIT
  • KIT/D814V
  • PRL2
  • PTP4A2
  • Self-renewal
  • Stem cell factor

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Kobayashi, M., Bai, Y., Dong, Y., Yu, H., Chen, S., Gao, R., ... Liu, Y. (2014). PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal. Stem Cells, 32(7), 1956-1967. https://doi.org/10.1002/stem.1672

PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal. / Kobayashi, Michihiro; Bai, Yunpeng; Dong, Yuanshu; Yu, Hao; Chen, Sisi; Gao, Rui; Zhang, Lujuan; Yoder, Mervin; Kapur, Reuben; Zhang, Zhong-Yin; Liu, Yan.

In: Stem Cells, Vol. 32, No. 7, 2014, p. 1956-1967.

Research output: Contribution to journalArticle

Kobayashi M, Bai Y, Dong Y, Yu H, Chen S, Gao R et al. PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal. Stem Cells. 2014;32(7):1956-1967. https://doi.org/10.1002/stem.1672
Kobayashi, Michihiro ; Bai, Yunpeng ; Dong, Yuanshu ; Yu, Hao ; Chen, Sisi ; Gao, Rui ; Zhang, Lujuan ; Yoder, Mervin ; Kapur, Reuben ; Zhang, Zhong-Yin ; Liu, Yan. / PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal. In: Stem Cells. 2014 ; Vol. 32, No. 7. pp. 1956-1967.
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AU - Kobayashi, Michihiro

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AU - Dong, Yuanshu

AU - Yu, Hao

AU - Chen, Sisi

AU - Gao, Rui

AU - Zhang, Lujuan

AU - Yoder, Mervin

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AU - Zhang, Zhong-Yin

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AB - 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

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