Mechanism of Regulation of Tyrosine Kinase Signaling

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Most of growth factor receptors transmit signals through tyrosine kinases which is encoded in the intracellular domain, or non-covalently associated JAK kinases like cytokine receptors. Constitutive activation of tyrosine kinase is frequently associated with neoplasm and leukemic development ; for example Bcr-Abl for chronicmyelogenous leukemia. Furthermore, downstream moleculessuchas Ras and STATs play important roles in intracellular signal transduction as well as cancer development.On the other hand, signal of cytokine plays important role on development of carcinogenesis and cancer through control of immune system as well as cell growth. About 20% of carcinoma has been thought to be derived from inflammation, however, there are many questions remained to be solved about inflammatory cytokines and their signals and carcinogenesis. Recently the TNF/NF-kB pathway has been implicated in inflammation-derived cancer, while we have investigated the STAT pathway, another important signal o … More f inflammatory cytokines. We have also investigated Ras/MAP kinase regulator Sprouty/Spred family proteins. Anti-tumor activity of SOCS1, a negative regulator of cytokine signaling, has been reported by many groups. SOCS1 may inhibit the development and/or progression of hepatocellular carcinoma, since SOCS1 expression is significantly reduced in HCC cells due to hyper-methylation of SOCS1 gene. In support of this, We have shown that SOCS1 heterozygous mice are hypersensitive to dimethylnitrosamine-induced hepatocarcinogenesis. In addition we have shown that reduction of SOCS1 expression is strongly associated with hepatitis and fibrosis. Thus, SOCS1 is a unique anti-oncogene that prevents inflammation-induced cancer. We also found that SOCS1 bound to oncogene product E7 of HPV, and induces degradation of E7, which results in the suppression of proliferation of cervical tumor cells, In addition, we found that Spred-1 interacts with not only Ras but also Rho and inhibits cell motility and metastasis of cancer cell. Less