Mechanism of Regulation of Tyrosine Kinase Signaling

酪氨酸激酶信号传导的调节机制

• 批准号: 12219216
• 负责人: YOSHIMURA Akihiko
• 金额: $ 109.76万
• 依托单位: Kyushu University (2001-2004)Kurume University (2000)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12219216/
• 关键词: tyrosine kinase; STAT; SOCS; inflammation; tyrosine phsphorylation; hepatitis; hepayoma; interferon; MITF; ユビキチン化; HPV; FGF受容体; Ras; MAPキナーゼ; EGF受容体; Raf; 細胞膜; シグナル伝達; JAK; CIS; サイトカイン; ノックアウトマウス; c-Cbl

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

大多数生长因子受体通过编码在细胞内域的酪氨酸激酶或像细胞因子受体这样的非共价相关的JAK激酶来传递信号。酪氨酸激酶的结构性激活经常与肿瘤和白血病的发展有关；例如，bcr-abl用于慢性粒细胞白血病。此外，下游分子Ras和STATs在细胞内信号转导和肿瘤发生发展中起重要作用，而细胞因子信号通过调控免疫系统和细胞生长在肿瘤发生和发展中发挥重要作用。近20%的肿瘤被认为是由炎症引起的，然而，关于炎症细胞因子及其信号与肿瘤发生的关系仍有许多问题需要解决。最近，肿瘤坏死因子/核因子-kB通路被认为与炎症性癌症有关，而我们已经研究了STAT通路，这是…的另一个重要信号更多的炎性细胞因子。我们还研究了RAS/MAP激酶调节蛋白Sprouty/Spred家族蛋白。SOCS1是一种细胞因子信号的负调控因子，其抗肿瘤活性已被多个研究小组报道。由于SOCS1基因高甲基化导致肝癌细胞SOCS1表达显著降低，SOCS1可能抑制肝细胞癌的发生和/或进展。为了支持这一点，我们已经证明了SOCS1杂合子小鼠对二甲基亚硝胺诱导的肝癌发生高度敏感。此外，我们还发现SOCS1表达降低与肝炎和纤维化密切相关。因此，SOCS1是一种独特的抗癌基因，可以预防炎症诱导的癌症。我们还发现SOCS1与HPV的癌基因产物E7结合，并诱导E7的降解，从而抑制宫颈癌细胞的增殖。此外，我们还发现Spred-1不仅与RAS相互作用，还与Rho相互作用，抑制癌细胞的运动和转移。较少

项目成果

Ohtsuka S, Takaki S, Yoshimura A, et al.: "SH2-B is Required for both Male and Female Reproduction Mol."Cell. Biol. 22. 3066-3077 (2002)

Ohtsuka S、Takaki S、Yoshimura A 等人：“男性和女性生殖分子都需要 SH2-B”细胞。

SOCS1 inhibits HPV-E7 mediated transformation by inducing degradation of E7 protein.

SOCS1 通过诱导 E7 蛋白降解来抑制 HPV-E7 介导的转化。

• 发表时间: 2004
• 期刊: Oncogene 23
• 作者: Kamio M;et al.
• 通讯作者: et al.

Saeki K, Miura Y, Aki D, Yoshimura A, et al.: "The B cell-specific major raft protein, Raftlin is necessary for the integrity of lipid raft and BCR signal transduction."EMBO J. 22. 3015-3026 (2003)

Saeki K、Miura Y、Aki D、Yoshimura A 等人：“B 细胞特异性主要筏蛋白 Raftlin 对于脂筏和 BCR 信号转导的完整性是必需的。”EMBO J. 22. 3015-3026 (

Sasaki, A, Taketomi T, Kato R, Yoshimura A, et al.: "Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1"Nature Cell Biol.. 5. 427-432 (2003)

Sasaki, A, Taketomi T, Kato R, Yoshimura A, et al.：“Mammalian Sprouty4 通过与 Raf1 结合抑制 Ras 独立的 ERK 激活”Nature Cell Biol.. 5. 427-432 (2003)

Shouda T, Yoshida T, Yoshimura A, et al.: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis"J. Clin. Invest.. 108. 1781-1788 (2001)

Shouda T、Yoshida T、Yoshimura A 等人：“诱导细胞因子信号调节剂 SOCS3/CIS3 作为治疗炎症性关节炎的治疗策略”J.