STE20-related kinase adaptor protein ? (STRAD?) regulates cell polarity and invasion through PAK1 signaling in LKB1-null cells.

ABSTRACT: LKB1 is a Ser/Thr kinase, and its activity is regulated by the pseudokinase, STE20-related adaptor ? (STRAD?). The STRAD?-LKB1 pathway plays critical roles in epithelial cell polarity, neuronal polarity, and cancer metastasis. Though much attention is given to the STRAD?-LKB1 pathway, the function of STRAD? itself, including a role outside of the LKB1 pathway, has not been well-studied. Data in Caenorhabditis elegans suggest that STRAD? has an LKB1-independent role in regulating cell polarity, and therefore we tested the hypothesis that STRAD? regulates cancer cell polarity and motility when wild-type LKB1 is absent. These results show that STRAD? protein is reduced in LKB1-null cell lines (mutation or homozygous deletion) and this partial degradation occurs through the Hsp90-dependent proteasome pathway. The remaining STRAD? participates in cell polarity and invasion, such that STRAD? depletion results in misaligned lamellipodia, improper Golgi positioning, and reduced invasion. To probe the molecular basis of this defect, we show that STRAD? associates in a complex with PAK1, and STRAD? loss disrupts PAK1 activity via Thr(423) PAK1 phosphorylation. When STRAD? is depleted, PAK1-induced invasion could not occur, suggesting that STRAD? is necessary for PAK1 to drive motility. Furthermore, STRAD? overexpression caused increased activity of the PAK1-activating protein, rac1, and a constitutively active rac1 mutant (Q61L) rescued pPAK(Thr423) and STRAD? invasion defects. Taken together, these results show that a STRAD?-rac1-PAK1 pathway regulates cell polarity and invasion in LKB1-null cells. It also suggests that while the function of LKB1 and STRAD? undoubtedly overlap, they may also have mutually exclusive roles.

SUBMITTER: Eggers CM 

PROVIDER: S-EPMC3365778 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature