Gab1 in UV-induced JNK Activation and Cell Apoptosis

紫外线（UV）是一种完全的致癌物质，可诱发皮肤癌。在众多影响中， 紫外线照射可迅速诱导哺乳动物细胞中c-Jun氨基末端蛋白激酶（JNK）的活化，并导致细胞凋亡。然而，紫外线照射激活JNK的分子机制知之甚少。我们已经发现，多底物适配器Gab 1起着至关重要的作用，在信号级联是由紫外线照射上调。Gab 1缺陷的成纤维细胞在通过UV光诱导JNK活性方面是有缺陷的，并且这种缺陷通过重新引入Gab 1而被挽救。我们还发现Gab 1与JNK组成性相关，紫外线照射细胞可诱导Gab 1的酪氨酸磷酸化。虽然初步数据表明肝细胞生长因子（HGF）受体c-Met可能发挥作用，但上游激酶Gab 1在紫外线照射下磷酸化， 仍有待明确识别。我们假设Gab 1是一种没有催化活性的支架蛋白，在细胞对UV暴露的反应中协调了酶和信号蛋白的独特组合，这代表了一种新的未探索的信号通路。我们将采取多学科的方法来阐明Gab 1活性在细胞对紫外线暴露的反应中的分子机制。我们的具体目标是：1）确定紫外线照射细胞中Gab 1上游的信号传导事件; 2）剖析Gab 1与JNK连接的生化机制; 3）检查Gab 1在细胞对紫外线的反应中的作用;以及4）确定Gab 1在小鼠中紫外线诱导的皮肤癌的发展中的作用。这项工作的长期目标是确定药物干预的靶点，以阻断紫外线引起的病理过程。

Ultraviolet (UV) light is a complete carcinogen that can induce skin cancer. Among many effects, UV irradiation rapidly induces activation of the c-Jun NH2-terminal protein kinase (JNK) in mammalian cells and causes cell apoptosis. However, the molecular mechanism for JNK activation by UV exposure is poorly understood. We have found that the multisubstrate adapter Gab1 plays an essential role in the signaling cascade that is upregulated by UV irradiation. Gab1-deficient fibroblast cells are defective in the induction of JNK activity by UV light, and this defect is rescued by re-introduction of Gab1. We have also found that Gab1 is constitutively associated with JNK, and that UV irradiation of cells induces tyrosine phosphorylation of Gab 1. Although preliminary data suggest a possible role for the hepatocyte growth factor (HGF) receptor c-Met, the upstream kinase(s) that phosphorylates Gab 1 in response to UV remains to be unequivocally identified. We hypothesize that Gab1, a scaffold protein without catalytic activity, orchestrates a unique combination of enzymes and signaling proteins in the cellular responses to UV exposure, which represents a novel and unexplored signaling pathway. We will take a multidisciplinary approach to elucidate the molecular mechanism for Gab 1 activity in cellular responses to UV exposure. Our specific aims are: 1) to define the signaling events upstream of Gab1 in UV-irradiated cells; 2) to dissect the biochemical machinery linking Gabl with JNK; 3) to examine the role of Gab1 in the cellular responses to UV light; and 4) to determine the role of Gab1 in the development of UV-induced skin cancer in mice. The long term goal of this work is to identify targets for pharmaceutical intervention to block pathological processes elicited by UV light.