| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2004: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2003: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| 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
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