Non-apoptotic functions of caspases

描述（由申请人提供）：细胞迁移和侵袭是肿瘤转移的关键方面，目前尚未完全了解。最近，我们发现凋亡调节因子caspase-8增强肿瘤细胞的迁移和侵袭，并调节细胞骨架调节的其他方面，包括calpain激活、Rac激活、板足的产生和细胞粘附。我们建议阐明caspase-8控制这些过程的机制。在第一个具体目标中，我们将确定caspase-8如何控制calpain的激活，特别是caspase-8对粘附复合物磷酸化和激活calpain的影响。在特定目标2中，我们将检验caspase-8通过刺激calpain介导的鸟嘌呤核苷酸交换因子（GEFs）对Rac的裂解和/或通过调节PI3-激酶的p85亚基来增强Rac活化的假设。特异性目的3利用一种基因定义和特征良好的人类乳腺癌小鼠模型来测试caspase-8对肿瘤转移的影响。Caspase-8在大多数人类肿瘤类型中均有表达。它可能协调凋亡和细胞运动信号的对立过程，这两个过程分别由成熟或未加工的酶进行。了解caspase-8的这种新功能对肿瘤发生和人类癌症治疗的影响是很重要的。

DESCRIPTION (provided by applicant): Cell migration and invasion are critical aspects of tumor metastasis that are incompletely understood. Recently, we have found that the apoptosis regulator, caspase-8, enhances cell migration and invasion of tumor cells, as well as modulating other aspects of cytoskeletal regulation, including calpain activation, Rac activation, generation of lamellipodia, and cell adhesion. We propose to elucidate the mechanisms whereby caspase-8 controls these processes. In the first specific aim, we will determine how caspase-8 controls calpain activation, particularly the effects of caspase-8 on the phosphorylation and activation of calpains by adhesion complexes. In specific aim 2, we will examine the hypotheses that caspase-8 enhances Rac activation by stimulating the calpain-mediated cleavage of guanine nucleotide exchange factors (GEFs) for Rac and/or by regulating the p85 subunit of PI3- Kinase. Specific aim 3 utilizes a genetically defined and well-characterized mouse model for human breast cancer to test the effects of caspase-8 on tumor metastasis. Caspase-8 expression is retained in most human tumor types. It may coordinate the opposing processes of apoptosis vs. cell motility signaling, which are carried out by the mature or unprocessed forms of the enzyme, respectively. It is important to understand the ramifications of this novel function of caspase-8 for oncogenesis and the treatment of human cancer.