The long-term objective of this proposal is to characterize the Cdc42- dependent signaling pathways required for the establishment of cell and actin polarity in eukaryotic cells, focusing on the roles of the p21- activated kinases (PAK), critical for mediating Cdc42 function. The experiments in Aim 1 propose to delineate the regulatory mechanisms required to properly localize PAKs to sites of polarized growth and to determine the biological consequences of PAK mislocalization. Specifically, these experiments will define both the upstream regulatory proteins and the putative regulatory sequences required for proper PAK localization.
Aim 2 is designed to identify downstream targets of the PAKs important for actin polarization and to characterize the functional significance of these polarity proteins. The budding yeast Saccharomyces cerevisiae has been chosen as a model system, allowing for a combination of yeast genetics and biochemical approaches to address the proposed research aims. Elucidating the signaling pathways directing cellular morphology may facilitate the development of strategies blocking the progression of pathological processes, dependent on Rho GTPase and PAK signaling. For example, the invasiveness and metastatic potential of tumor cells, influenced by changes in cell motility and adhesion, could potentially be abrogated by manipulation of these signaling pathways.
| Wild, Angela C; Yu, Jong W; Lemmon, Mark A et al. (2004) The p21-activated protein kinase-related kinase Cla4 is a coincidence detector of signaling by Cdc42 and phosphatidylinositol 4-phosphate. J Biol Chem 279:17101-10 |
