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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

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

Eggers Carrie M CM Kline Erik R ER Zhong Diansheng D Zhou Wei W Marcus Adam I AI

The Journal of biological chemistry 20120406 22

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, a ...[more]

PMID: 22493453

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Project description:The myocardium undergoes extensive metabolic and energetic remodeling during the progression of cardiac disease. Central to remodeling are changes in the adenine nucleotide pool. Fluctuations in these pools can activate AMP-activated protein kinase (AMPK), the central regulator of cellular energetics. Binding of AMP to AMPK not only allosterically activates AMPK but also promotes phosphorylation of AMPK by an upstream kinase complex, LKB1/Mo25/STRAD (liver kinase B 1, mouse protein 25, STE-related adaptor protein). AMPK phosphorylation by the LKB1 complex results in a substantial increase in AMPK activity. Molecular targeting by the LKB1 complex depends on subcellular localization and transcriptional expression. Yet, little is known about the ability of the LKB1 complex to modulate targeting of AMPK after activation. Accordingly, we hypothesized that differing stoichiometric ratios of LKB1 activator complex to AMPK would uniquely impact myofilament function. Demembranated rat cardiac trabeculae were incubated with varying ratios of the LKB1 complex to AMPK or the LKB1 complex alone. After incubation, we measured the Ca(2+) sensitivity of tension, rate constant for tension redevelopment, maximum tension generation, length-dependent activation, cooperativity, and sarcomeric protein phosphorylation status. We found that the Ca(2+) sensitivity of tension and cross-bridge dynamics were dependent on the LKB1 complex/AMPK ratio. We also found that the LKB1 complex desensitizes and suppresses myofilament function independently of AMPK. A phospho-proteomic analysis of myofilament proteins revealed site-specific changes in cardiac Troponin I (cTnI) phosphorylation, as well as a unique distribution of cTnI phosphospecies that were dependent on the LKB1 complex/ AMPK ratio. Fibers treated with the LKB1 complex alone did not alter cTnI phosphorylation or phosphospecies distribution. However, LKB1 complex treatment independent of AMPK increased phosphorylation of myosin-binding protein C. Therefore, we conclude that the LKB1/AMPK signaling axis is able to alter muscle function through multiple mechanisms.

Dataset Information

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

Publications

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

Similar Datasets

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