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.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Nabinger
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshimoto
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Sisi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Chonghua
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Yuanshu
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lujuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yashiro-Ohtani
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.affiliation: Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Daniel Lacorazza
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017874:Immediate-Early Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D019009:Proto-Oncogene Proteins c-kit; D017027:Protein Tyrosine Phosphatases; C111533:Ptp4a2 protein, mouse
keywords: Early T lineage progenitors; Notch; PRL2; T cell progenitors; Thymopoiesis; c-Kit