STE20-related Kinase Adaptor Protein α (STRADα) Regulates Cell Polarity and Invasion through PAK1 Signaling in LKB1-null Cells
STE20-related Kinase Adaptor Protein α (STRADα) Regulates Cell Polarity and Invasion through PAK1 Signaling in LKB1-null Cells
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DOI：
10.1074/jbc.m111.316422
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发表时间：
2012-05-25
影响因子：
4.8
通讯作者：
Marcus, Adam I.
中科院分区：
文献类型：
--
作者：
Eggers, Carrie M.;Kline, Erik R.;Marcus, Adam I.
LKB1是一种丝氨酸/苏氨酸激酶，其活性受假激酶ste20相关接头α (STRAD α)调控。STRAD α - lkb1通路在上皮细胞极性、神经元极性和肿瘤转移中起关键作用。尽管人们对STRAD α -LKB1通路给予了很多关注，但STRAD α本身的功能，包括在LKB1通路之外的作用，尚未得到很好的研究。在秀丽隐杆线虫中的数据表明，STRAD α在调节细胞极性方面具有与LKB1无关的作用，因此我们验证了STRAD α在野生型LKB1缺失时调节癌细胞极性和运动的假设。这些结果表明，STRAD α蛋白在lkb1缺失的细胞系中（突变或纯合缺失）减少，这种部分降解是通过依赖hsp90的蛋白酶体途径发生的。剩余的STRAD α参与细胞极性和侵袭，因此STRAD α的缺失导致板足错位、高尔基定位不当和侵袭减少。为了探究这一缺陷的分子基础，我们发现STRAD α与PAK1结合在一个复合物中，STRAD α的缺失通过Thr(423) PAK1磷酸化破坏PAK1的活性。当STRAD α缺失时，PAK1诱导的侵袭就不会发生，这表明STRAD α是PAK1驱动运动所必需的。此外，STRAD α过表达导致pak1激活蛋白rac1的活性增加，一个组成型活性rac1突变体（Q61L）挽救了pPAK（Thr423）和STRAD α侵袭缺陷。综上所述，这些结果表明STRAD α -rac1- pak1通路调节lkb1缺失细胞的细胞极性和侵袭。这也表明，虽然LKB1和STRAD α的功能无疑是重叠的，但它们也可能具有互斥的作用。
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.