| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2005: ¥9,100,000 (Direct Cost: ¥9,100,000)
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| Research Abstract |
Protein-tyrosine kinases (PTKs) play essential roles in transmitting signals from microenvironments to intracellular compartments. PTKs phosphorylate themselves and/or adaptors termed docking proteins to recruit downstream effectors. Previously, we identified Dok-1 as a novel docking protein and found that Dok-1 and its closely related protein Dok-2 play essential roles for homeostasis of myelopoiesis and inhibition of leukemogenesis by negatively regulating downstream signaling of cytokine or LPS receptors.
In this research, we investigated the role of Dok-1 and Dok-2 in T cells and found that they play an essential role in negative regulation of T cell receptor-mediated signaling and mice lacking these proteins develop lupus-like renal disease. Interestingly, SH2 target motifs in the COOH-terminal moiety, which are crucial for the known adaptor function, are dispensable for this negative regulation, suggesting an as yet unidentified mechanism. In addition, we revealed that another Dok
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-family protein Dok-3, which is preferentially expressed in hematopoietic cells like Dok-1/2, sequestrates Grb2, unlike Dok-1/2, and inhibits the Ras-Erk pathway. We are investigating the role of Dok-1/2/3 in hematopoietic cells.
The latest member of Dok-family was identified in this research; we named it Dok-7. To our surprise, although Dok-7 appears to be an adaptor, it activates MuSK, a muscle-specific receptor PTK, which is localized at the postsynaptic region of neuromuscular junction (NMJ) and essential for formation of NMJ, a synapse that links a motor nerve with a myotube. Furthermore, we found that Dok-7 is essential for activation of MuSK in myotubes and plays an essential role in NMJ formation as MuSK does. In collaboration with David Beeson, Angela Vincent, and their colleagues, we also revealed that Dok-7 mutations underlie a certain type of congenital myasthenic syndromes.
These findings significantly contribute to our understanding of physiological and pathophysiological roles of the Dok-family proteins. Less
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