Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors

Michihiro Kobayashi; Sarah c. Nabinger; Yunpeng Bai; Momoko Yoshimoto; Rui Gao; Sisi Chen; Chonghua Yao; Yuanshu Dong; Lujuan Zhang; Sonia Rodriguez; Yumi Yashiro-Ohtani; Warren S. Pear; Nadia Carlesso; Mervin C. Yoder; Reuben Kapur; Mark H. Kaplan; Hugo Daniel Lacorazza; Zhong Yin Zhang; Yan Liu

doi:10.1002/stem.2559

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors

Michihiro Kobayashi, Sarah c. Nabinger, Yunpeng Bai, Momoko Yoshimoto, Rui Gao, Sisi Chen, Chonghua Yao, Yuanshu Dong, Lujuan Zhang, Sonia Rodriguez, Yumi Yashiro-Ohtani, Warren S. Pear, Nadia Carlesso, Mervin C. Yoder, Reuben Kapur, Mark H. Kaplan, Hugo Daniel Lacorazza, Zhong Yin Zhang^*, Yan Liu

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053–1064.

Original language	English (US)
Pages (from-to)	1053-1064
Number of pages	12
Journal	Stem Cells
Volume	35
Issue number	4
DOIs	https://doi.org/10.1002/stem.2559
State	Published - Apr 1 2017

Funding

This work was supported in part by National Institutes of Health Grant CA69202 (Z.-Y.Z.), Department of Defense Grant W81XWH-13-1-0187 (Y.L.), a St. Baldrick's Foundation Scholar Award (Y.L.), an Elsa Pardee Foundation New Investigator Award (Y.L.), Leukemia Research Foundation New Investigator Award (Y.L.), an Alex's Lemonade Stand Grant (Y.L.), a Children's Leukemia Research Association Grant (Y.L.), and American Cancer Society Institutional Research Grants (Y.L. and M.K.). This work was supported by a Project Development Team within the ICTSI NIH/NCRR Grant Number UL1TR001108. We thank Marilyn Wales for helping in the preparation of the manuscript.

Keywords

Early T lineage progenitors
Notch
PRL2
T cell progenitors
Thymopoiesis
c-Kit

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/stem.2559

Cite this

Kobayashi, M., Nabinger, S. C., Bai, Y., Yoshimoto, M., Gao, R., Chen, S., Yao, C., Dong, Y., Zhang, L., Rodriguez, S., Yashiro-Ohtani, Y., Pear, W. S., Carlesso, N., Yoder, M. C., Kapur, R., Kaplan, M. H., Daniel Lacorazza, H., Zhang, Z. Y., & Liu, Y. (2017). Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors. Stem Cells, 35(4), 1053-1064. https://doi.org/10.1002/stem.2559

@article{51fb89539c2444d29055afd78d24c6c7,

title = "Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors",

abstract = "The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053–1064.",

keywords = "Early T lineage progenitors, Notch, PRL2, T cell progenitors, Thymopoiesis, c-Kit",

author = "Michihiro Kobayashi and Nabinger, {Sarah c.} and Yunpeng Bai and Momoko Yoshimoto and Rui Gao and Sisi Chen and Chonghua Yao and Yuanshu Dong and Lujuan Zhang and Sonia Rodriguez and Yumi Yashiro-Ohtani and Pear, {Warren S.} and Nadia Carlesso and Yoder, {Mervin C.} and Reuben Kapur and Kaplan, {Mark H.} and {Daniel Lacorazza}, Hugo and Zhang, {Zhong Yin} and Yan Liu",

note = "Publisher Copyright: {\textcopyright} 2016 AlphaMed Press",

year = "2017",

month = apr,

day = "1",

doi = "10.1002/stem.2559",

language = "English (US)",

volume = "35",

pages = "1053--1064",

journal = "Stem Cells",

issn = "1066-5099",

publisher = "Oxford University Press",

number = "4",

}

Kobayashi, M, Nabinger, SC, Bai, Y, Yoshimoto, M, Gao, R, Chen, S, Yao, C, Dong, Y, Zhang, L, Rodriguez, S, Yashiro-Ohtani, Y, Pear, WS, Carlesso, N, Yoder, MC, Kapur, R, Kaplan, MH, Daniel Lacorazza, H, Zhang, ZY & Liu, Y 2017, 'Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors', Stem Cells, vol. 35, no. 4, pp. 1053-1064. https://doi.org/10.1002/stem.2559

TY - JOUR

T1 - Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors

AU - Kobayashi, Michihiro

AU - Nabinger, Sarah c.

AU - Bai, Yunpeng

AU - Yoshimoto, Momoko

AU - Gao, Rui

AU - Chen, Sisi

AU - Yao, Chonghua

AU - Dong, Yuanshu

AU - Zhang, Lujuan

AU - Rodriguez, Sonia

AU - Yashiro-Ohtani, Yumi

AU - Pear, Warren S.

AU - Carlesso, Nadia

AU - Yoder, Mervin C.

AU - Kapur, Reuben

AU - Kaplan, Mark H.

AU - Daniel Lacorazza, Hugo

AU - Zhang, Zhong Yin

AU - Liu, Yan

PY - 2017/4/1

Y1 - 2017/4/1

N2 - The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053–1064.

AB - The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053–1064.

KW - Early T lineage progenitors

KW - Notch

KW - PRL2

KW - T cell progenitors

KW - Thymopoiesis

KW - c-Kit

UR - http://www.scopus.com/inward/record.url?scp=85016111035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016111035&partnerID=8YFLogxK

U2 - 10.1002/stem.2559

DO - 10.1002/stem.2559

M3 - Article

C2 - 28009085

AN - SCOPUS:85016111035

SN - 1066-5099

VL - 35

SP - 1053

EP - 1064

JO - Stem Cells

JF - Stem Cells

IS - 4

ER -

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this