| Budget Amount *help |
¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
Janus kinases (Jaks) regulate cellular processes involved in cell growth, differentiation and transformation through their association with cytokine receptors. Recently, Jak-binding protein (JAB) was identified as a JAK inhibitor. We demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2, whose phosphorylation is required for activation of kinase activity.
Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo. Tyk2-deficient mice show no overt developmental abnormalities, however they display a lack of responsiveness to a small amount of IFNγ, although a high concentration of IFNγ can fully transduce its signal even in the absence of tyk2. Furthermore, IL-12-induced T cell function is defective in these mice. In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro. These observations demonstrate that tyk2 plays only a restricted role in mediating IFNγ-dependent signaling, whilst being required in mediating IL-12-dependent biological responses.
One member of the STAT family of proteins is STAT3, which is mainly activated by IL-6 family of cytokines, epidermal growth factor, and leptin. Like other members of the STAT family, STAT3 is tyrosine-phosphorylated by Jak kinases, upon which it dimerizes, and translocates into the nucleus to activate target genes. We provided evidence that the inhibitory action of estrogen receptor on STAT3 activity was due to direct physical interactions between STAT3 and estrogen receptor, which represents a novel form of cross-talk between STAT3 and ER signaling pathways.
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