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2004 Fiscal Year Final Research Report Summary

Lnk family adaptor proteins in the development and regulation of immune-competent cells

Research Project

Project/Area Number 15390157
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionThe University of Tokyo

Principal Investigator

TAKAKI Satoshi  The University of Tokyo, The Institute of Medical Science, Associate professor, 医科学研究所, 助教授 (10242116)

Project Period (FY) 2003 – 2004
KeywordsAdaptor protein / Cell proliferation / Signal transduction / Mast cell / B cell / Actin cytoskeleton / Regenerative medicine / Bone marrow transfer
Research Abstract

Lnk, SH2-B and APS form an intracellular adaptor protein family. APS-/-mice were viable, fertile, and showed no abnormalities or growth retardation. Immunologically, APS-/-mice showed normal development and distribution of lymphocytes and myeloid cells, except for increased numbers of B-1 cell in the peritoneal cavity. F-actin contents after BCR stimulation was decreased in APS-/-B-1 cells compared to wild-type cells. Lnk, SH2-B, and APS are all expressed in mast cells. We established bone marrow-derived mast cells (BMMCs) from lnk^<-/->, SH2-B^<-/-> and APS^<-/-> mice. Proliferation and various function of BMMCs were normal in the absence of Lnk or SH2-B. In contrast, APS-deficient BMMCs showed augmented degranulation after cross-linking FcεRI. APS-deficient cells showed reduced actin assembly at steady state. Our results suggest potential roles of APS in controlling actin cytoskeleton and magnitude of degranulation in mast cells.
While Lnk negatively regulates B-lymphopoiesis and earl … More y hematopoiesis, the molecular mechanism underlying Lnk-mediated regulation remains obscure. We found Lnk controls actin reorganization activated by receptor tyrosine kinases (RTKs), thereby regulating cell division and migration. Lnk-expressing fibroblasts showed flattened, spreading morphology and prominent actin polymerization that resulted in multinuclear cell formation due to impaired cytokinesis. Lnk was co-immunoprecipitated with Rac, Vav, PAK and filamin A, which suggested the formation of a cytoskeletal regulatory protein complex supported by Lnk. Thus, Lnk functions as a novel scaffold molecule that links RTKs with cytoskeletal regulatory components.
The number of hematopoietic stem cells (HSCs) in the bone marrow is developmentally regulated. Lnk-/-mice display more than 10-fold increase of functional HSCs in number in the adult bone marrow. In addition, a clonal analysis suggests that a part of Lnk-deficient HSCs are highly repopulating stem cells, manifested by higher degree of self-renewal capacity. Less

  • Research Products

    (9 results)

All 2005 2004 2003

All Journal Article (7 results) Book (2 results)

  • [Journal Article] APS, an adaptor molecule containing PH and SH2 domains, has a negative regulatory role in B cell proliferation.2005

    • Author(s)
      Iseki, M. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 330

      Pages: 1005-1013

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice.2005

    • Author(s)
      Ema, H.et al.
    • Journal Title

      Developmental Cell (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice.2005

    • Author(s)
      Ema, H.et al.
    • Journal Title

      Developmental Cell (In press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Roles of a conserved family of adaptor proteins, Lnk, SH2-B, and APS, for mast cell development, growth, and functions.2004

    • Author(s)
      Kubo-Akashi, C. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 315

      Pages: 356-362

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Increased numbers of B-1 cells and enhanced responses against TI-2 antigen in mice lacking APS, an adaptor molecule containing PH and SH2 domains.2004

    • Author(s)
      Iseki, M. et al.
    • Journal Title

      Mol.Cell.Biol. 24

      Pages: 2243-2250

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Regulation of hematopoetic development in the aorta-gonad-mesonephros region mediated by Lnk adaptor protein.2003

    • Author(s)
      Nobuhisa, I. et al.
    • Journal Title

      Mol.Cell.Biol. 23

      Pages: 8486-8494

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Increased insulin sensitivity and hypoinsulinemia in APS knockout mice.2003

    • Author(s)
      Minami, A. et al.
    • Journal Title

      Diabetes 52

      Pages: 2657-2665

    • Description
      「研究成果報告書概要(和文)」より
  • [Book] 日本臨床増刊号「臨床免疫学-基礎研究の進歩と最新の臨床-」上巻 B細胞の分化・活性化における補助シグナル2005

    • Author(s)
      高木智(分担執筆)
    • Total Pages
      710
    • Publisher
      日本臨床社
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] Clinical Immunology (1) "Costimulation signals in B cell maturation and activation"2005

    • Author(s)
      Takaki S.
    • Total Pages
      710
    • Publisher
      Nippon-rinsho Co.
    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2006-07-11  

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