title: STE20-related kinase adaptor protein α (STRADα) 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 α (STRADα). The STRADα-LKB1 pathway plays critical roles in epithelial cell polarity, neuronal polarity, and cancer metastasis. Though much attention is given to the STRADα-LKB1 pathway, the function of STRADα itself, including a role outside of the LKB1 pathway, has not been well-studied. Data in Caenorhabditis elegans suggest that STRADα has an LKB1-independent role in regulating cell polarity, and therefore we tested the hypothesis that STRADα regulates cancer cell polarity and motility when wild-type LKB1 is absent. These results show that STRADα 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 STRADα participates in cell polarity and invasion, such that STRADα depletion results in misaligned lamellipodia, improper Golgi positioning, and reduced invasion. To probe the molecular basis of this defect, we show that STRADα associates in a complex with PAK1, and STRADα loss disrupts PAK1 activity via Thr(423) PAK1 phosphorylation. When STRADα is depleted, PAK1-induced invasion could not occur, suggesting that STRADα is necessary for PAK1 to drive motility. Furthermore, STRADα overexpression caused increased activity of the PAK1-activating protein, rac1, and a constitutively active rac1 mutant (Q61L) rescued pPAK(Thr423) and STRADα invasion defects. Taken together, these results show that a STRADα-rac1-PAK1 pathway regulates cell polarity and invasion in LKB1-null cells. It also suggests that while the function of LKB1 and STRADα undoubtedly overlap, they may also have mutually exclusive roles.
authors.affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Eggers
authors.forename: Erik R
authors.initials: ER
authors.lastname: Kline
authors.forename: Diansheng
authors.initials: D
authors.lastname: Zhong
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Adam I
authors.initials: AI
authors.lastname: Marcus
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D001483:Base Sequence; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology*; D017931:DNA Primers; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; C109163:STK24 protein, human; D000099317:Hippo Kinases; C515903:PAK1 protein, human; C109790:STK11 protein, human