Role of Anti-Apoptic Aaction of Focal Adhesion Kinase (FAK)

粘着斑激酶 (FAK) 的抗凋亡作用的作用

• 批准号: 12672118
• 负责人: KASAHARA Tadashi
• 金额: $ 2.18万
• 依托单位: Kyoritsu College of Pharmacy
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672118/
• 关键词: apoptosis induction; signal trasduction; oxidative stress; focal adhesion kinase (FAK); PI3-kinase; survival pathway; caspase family; anti-apoptosis; アポトーシス; 抗アポトーシス作用; 抗アポートシス作用

Focal adhesion kinase (FAK) is a tyrosine kinase expressed in many type of cells, especially in cancer cells such as invasive or metastatic colon carcinomas, breast tumors, oral cancers. FAK plays an important role in cell growth, survival, and migration, thus rendering a critical role in development of tumor cells. FAK is tyrosine-phosphorylated and activated by many types of stimuli, such as bombesin, bradykinin, platelet-derived growth factor, hepatocyte growth factor, insulin, chemokines. We found that FAK is tyrosine-phosphorylated by reactive oxygen species and the tyrosine-phosphorylation was prerequisite for the antiapoptotic function of FAK. In addition, PKB/Akt pathway has been implicated in the survival signal of FAK. We identified that FAK overexpression leads to constitutive activation of survival pathwayand anti-apoptotic role in the apoptosis induced by oxidative stress, anti-cancer drug, irradiation in anchorage-independent cells, IIL-60. Other some protein tyrosine kinase overexpression and/or deregulation also lead to constitutive downstream kinase activation, infinite proliferation and oncogenic transformation. We assumed that FAK may be like an oncogene and become potential targets by anti-cancer strategies, particularly emphasizing the role of FAK linking to survival pathway.

局灶黏附激酶（Focal adhesion kinase， FAK）是一种酪氨酸激酶，在许多类型的细胞中表达，尤其是在侵袭性或转移性结肠癌、乳腺癌、口腔癌等癌细胞中。FAK在细胞生长、存活和迁移中起着重要作用，因此在肿瘤细胞的发育中起着至关重要的作用。FAK被酪氨酸磷酸化，并被许多类型的刺激激活，如bombesin，舒缓激肽，血小板衍生生长因子，肝细胞生长因子，胰岛素，趋化因子。我们发现FAK被活性氧酪氨酸磷酸化，酪氨酸磷酸化是FAK抗凋亡功能的先决条件。此外，PKB/Akt通路与FAK的存活信号有关。我们发现FAK过表达导致生存途径的组成性激活，并在氧化应激、抗癌药物、锚定非依赖性细胞辐照、il -60诱导的细胞凋亡中发挥抗凋亡作用。其他一些蛋白酪氨酸激酶过表达和/或失调也会导致组成性下游激酶激活、无限增殖和致癌转化。我们假设FAK可能像致癌基因一样，成为抗癌策略的潜在靶点，特别强调FAK与生存途径的联系。

项目成果

Matsui S et al.: "LIM kinase 1 modulates opsonized zymosan-triggered activation of macrophage-like U937 cells. Possible involvement of phosphorylation of cofilin and reorganization of actin cytoskeleton"J Biol Chem.. 277(1). 544-9 (2002)

Matsui S 等人：“LIM 激酶 1 调节调理酶聚糖触发的巨噬细胞样 U937 细胞的激活。可能涉及丝切蛋白的磷酸化和肌动蛋白细胞骨架的重组”J Biol Chem.. 277(1)。

Matsui S, Adashi R, Kasahara T et al.: "U73122 inhibits the dephosphorylationa dn traslocation of cofilin in activated macrophage-like U937 cells"Cell Signalling. 13(1). 17-22 (2001)

Matsui S、Adashi R、Kasahara T 等人：“U73122 抑制激活的巨噬细胞样 U937 细胞中肌动蛋白丝切蛋白的去磷酸化和易位”Cell Signalling。

Sonoda Y et al.: "Anti-apoptotic role of focal adhesion kinase (FAK) : Induction of Inhibitor-of-Apoptosis Proteins and Apoptosis Suppression by the Overexpression of FAK ina"J Biol Chem. 275:5. 16309-16315 (2000)

Sonoda Y 等人：“粘着斑激酶 (FAK) 的抗凋亡作用：凋亡抑制剂蛋白的诱导和 FAK 过表达的凋亡抑制”J Biol Chem。

Mori M, Terui Y, Kasahara T et al.: "Antitumor effect of b2-microgiobufin in leukemic cell-bearing mice via apoptosis-inducing activity : activation of caspase-3 and NF-kB"Cancer Res.. 61(11). 4414-4417 (2001)

Mori M、Terui Y、Kasahara T 等人：“b2-microgiobufin 通过细胞凋亡诱导活性对白血病细胞小鼠产生抗肿瘤作用：激活 caspase-3 和 NF-kB”Cancer Res.. 61(11)。

Sonoda Y, Yamamoto D, Kasahara T et al.: "FTY72O, anovel immunosuppressive agent, induces apoptosis in human glioma cells"Blochem Blophys Res Commun. 281(2). 282-288 (2001)

Sonoda Y、Yamamoto D、Kasahara T 等人：“FTY72O，新型免疫抑制剂，诱导人神经胶质瘤细胞凋亡”Blochem Blophys Res Commun。