Regulation of signal transduction for cell growth and differentiation by Lnk-family adaptor proteins

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Lnk is an adaptor protein expressed mainly in lymphocytes. Lnk forms part of an adaptor protein family together with APS and SH2-B, whose members share the presence of a homologous N-terminal domain with putative proline-rich protein interaction motifs, followed by PH and SH2 domains, and a conserved C-terminal tyrosine phosphorylation site.Lnk regulates B cell production by negatively controlling pro-B cell expansion. Lnk-deficient mice show enhanced B cell production due to the hypersensitivity of B cell precursors to SCF, a c-Kit ligand. In addition, the numbers of hematopoietic progenitors in the bone marrow increase in lnk-deficient mice. Competitive repopulation assays demonstrate that the ability of hematopoietic progenitors to generate various lineages of hematopoietic cells is greatly enhanced by the absence of Lnk. Reduction of c-Kit expression by the introduction of the Kit^W mutation on a lnk^<-/-> background partially but significantly normalized B cell overproduction. In contrast, an enhanced ability of HSCs was not normalized, suggesting involvement of as yet unidentified mechanism(s) in addition to the enhanced c-Kit signaling. Lymphocyte production was impaired in a dose dependent manner upon overexpression of Lnk in lymphoid cells by transgenic approach. Lnk regulates lymphopoiesis and mature B cell subpopulations by regulating c-Kit-indipendent as well as c-Kit-dependent signaling pathways. Lnk is phosphorylated by and associates with c-Kit. Lnk selectively inhibits c-Kit-mediated proliferation by inhibiting tyrosine phosphorylation of Gab2 and activation of the MAPK cascade.We also generated SH2-B-deficient mice and APS-deficient mice and investigated physiological roles of SH2-B and APS in vivo.