| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
Lnk is an adaptor protein that appears to be involved in signal transduction in lymphocytes, based on its expression in T cells and B cells and possible interaction with Grb2, PLCγ and PI3K.To illuminate the importance of Lnk in signal transduction, we generated Lnk-deficient mice. Animals lacking Lnk expression did not show any overt developmental abnormalities and were normal in size, activity, and fertility. Whereas T-cell development in the thymus was not affected, pre-B cells and immature B cells accumulated in the spleens of Lnk-/-mice. In the bone marrow, a significant expansion of the pro-B cell fraction leading to a proportionate increase in the representation of more mature B-cell precursors was observed. This increase in B-cell precursors resulted from enhanced proliferation, due to intrinsic defects within B cell precursors as demonstrated by bone marrow transfer experiments. Proliferative responses mediated by c-Kit were augmented in the Lnk-/-immature bone marrow cells. Our results suggest a specific, cell-autonomous function of Lnk in limiting B-lymphopoiesis. Further characterization of Lnk-/-mice also revealed that the full length Lnk protein is nearly twice the size of the previously published protein. Full length Lnk contains a proline-rich region followed by a PH domain, an SH2 domain, and a conserved motif harboring a candidate tyrosine phosphorylation site. Lnk is a representative of a multigene family whose members presumably function as a negative regulator of signaling mediated by tyrosine kinases.
We tried to identify another member of the adaptor protein family and isolated the mouse APS.APS is expressed in brain, kidney, muscle, and in B cells in spleen. APS is tyrosine phosphorylated at the C-terminal phosphorylation site by crosslinking of sIgM of B cells. APS is likely to play a role in signaling in B cells.
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