Molecular dissection of divergent members of a new class of regulators of microtubule dynamics
Our focus on identification of intracellular proteins with potential functions during signal transduction and growth control led to the identification of Oncoprotein 18 (Op18, also termed Stathmin).
Extensive phosphorylation and up-regulation of Op18 in some human malignancies suggested a role in cell signaling. We have now identified the function of Op18 as a phosphorylation-responsive regulator of microtubule dynamics and linked Op18 phosphorylation to regulation of microtubule dynamics in response to signal transduction events.
It seems likely that this function is shared by neural members of the Op18/Stathmin family. Our molecular dissection shows that Op18 has the potential to exert multiple tubulin/microtubule-directed activities. In the present application I propose strategies to:
I. Determine the importance of site-specific Op18 phosphorylation during signal transduction events using our newly developed gene product-replacement strategy.
II. To use the gene product-replacement strategy to dissect the physiological relevance of previously identified tubulin/microtubule directed activities of Op18 family members.
III. Studies of functional interplay between Op18 and the interacting CDK inhibitor p27kip1.
VI. To dissect the function of the parasite derived Sm16 protein that has been described as Op18-like.