Apoptosis is a physiological process of cell death which plays a critical role in normal development, maintenance of tissue homeostasis, and elimination of damaged or unwanted cells. Malfunction of the regulatory mechanisms controlling apoptosis has been implicated in a variety of human diseases, including cancer and neurodegenerative disorders. It is also becoming clear that cell death and cell survival are mechanistically coupled. The balance between proapoptotic processes and antiapoptotic survival signals determines whether cells live or die. Therefore, understanding the intricate regulatory networks that control cell death and survival may allow us to rationally manipulate apoptotic machinery for therapeutic interventions. This proposal examines a novel mechanism that controls the signaling of a key death promoting kinase, ASK1 (Apoptosis Signal regulating Kinase 1). ASK1 is a pivotal component of cytokine and stress induced apoptotic signaling pathways. Our preliminary data indicate that ASK1 is specifically associated with 14 3 3, a family of phosphoserine binding proteins. Significantly, a point mutation at Ser967 that abolishes phosphorylation and 14 3 3 binding accelerates ASK1 induced apoptosis while overexpression of 14 3 3 inhibits ASK1 proapoptotic activity. These findings led to our hypothesis that 14 3 3 controls the death promoting activity of ASK1, and this death inhibitory function is regulated by an unidentified kinase that phosphorylates Ser967. Therefore, Ser967 may serve as a point of crosstalk between cell survival signaling and the ASK1mediated apoptotic pathway. The current research will test these hypotheses. The main goals are: (i) To determine the role of 14 3 3 in ASKl mediated apoptosis. (ii) To identify the kinase that phosphorylates Ser967 of ASK1 in response to survival signals. (iii) To dissect and identify ASK1 effector pathway(s) leading to cell death. Because ASK1 represents a general mediator of multiple apoptotic signals, deciphering how ASK1 is regulated by pro and antiapoptotic mechanisms may provide critical insights into how cell survival is maintained and may lead to novel molecular targets for drug discovery.
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