This program project application focuses on signaling networks that regulate cell survival and motility/invasion. Eight Burnham Institute laboratories participate, and multidisciplinary approaches will be used. Cell survival and motility signals are intimately connected and can be coordinately reprogrammed, for example by certain transforming mutations in cancer. Many of these pathways culminate in activation of the small GTPase Rac and the downstream Jun N-terminal kinase (JNK) pathway. Rac is a central coordinator of the actin cytoskeleton and controls both cell migration/invasion and JNK. Depending on the circumstances, JNK can either support cell survival or promote cell death, and can also affect invasiveness through matrix metalloproteinase expression. Dr. Vuori will work on the regulation of Rac by the adaptor protein Crk and its partner DOCK180. Dr. Pasquale will study SHEP1, which binds receptor tyrosine kinases, Ras GTPases that promote integrin activity, and the docking protein p130Cas. p130Cas functions upstream of the Crk/DOCK180 complex, and mediates integrin-induced Rac and JNK activation. Thus, SHEP1 may integrate diverse cellular signals related to cell survival, adhesion, and migration. Dr. Ruoslahti will examine an adhesion-dependent survival pathway that involves the novel mitochondrial protein Bit1, which promotes cell death when is released in the cytoplasm and forms a complex with the transcriptional regulator AES. The regulation of the Bit1/AES complex and its relationship with other survival/apoptosis pathways will be investigated. Dr. Feng will study the docking protein Gab1, which he has recently implicated in JNK activation and apoptosis caused by UV irradiation. Gab1 may be a switch that turns on the pro-apoptotic mode of JNK activation. Two core components will enable specialized functional studies, one in structural biology of protein-protein interfaces and the other in genetic mouse tumor models. The diverse expertise of the participating laboratories and the resources provided by the cores will synergistically contribute to the characterization of novel signaling connections and the discovery of strategies to control cell survival and invasion pathways that are deregulated in cancer. These studies may allow future development of small molecules that can disrupt pathologic signals by targeting protein interfaces.
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