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

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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