STE20-related Kinase Adaptor Protein α (STRADα) Regulates Cell Polarity and Invasion through PAK1 Signaling in LKB1-null Cells

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