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，尚未完全了解。最近，我们发现凋亡调节因子caspase-8可增强肿瘤细胞的迁移和侵袭，以及调节细胞骨架调节的其他方面，包括钙蛋白酶激活、Rac激活、板状伪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。在第一个具体的目标，我们将确定caspase-8如何控制钙蛋白酶激活，特别是caspase-8的磷酸化和激活钙蛋白酶的粘附复合物的影响。在具体的目标2中，我们将研究caspase-8通过刺激钙蛋白酶介导的鸟嘌呤核苷酸交换因子（GEF）对Rac的切割和/或通过调节PI 3-激酶的p85亚基来增强Rac激活的假设。具体目标3利用遗传定义和良好表征的人乳腺癌小鼠模型来测试半胱天冬酶-8对肿瘤转移的影响。Caspase-8表达在大多数人类肿瘤类型中保留。它可以协调细胞凋亡与细胞运动信号传导的相反过程，这分别由成熟或未加工形式的酶进行。重要的是要了解这种新的caspase-8的功能，肿瘤发生和人类癌症的治疗的分支。

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.