PDF(Pubmed)
Abstract：
The remodeling and stiffening of the extracellular matrix (ECM) is a well-recognized modulator of breast cancer progression. How changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remain poorly characterized. Here, we describe a new role for the autophagy-inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We show that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs) and as a consequence impedes cell contraction and migration, independent of its role in autophagy. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK-mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid-liquid phase separation of PXN, impairing FA assembly, which in turn alters the mechanical properties of breast cancer cells and their response to mechanical stimuli. ULK1/2 and the well-characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Taken together, our study reveals ULK1/2 as important regulator of PXN-dependent mechanotransduction.
摘要：
细胞外基质（ECM）的重塑和硬化是公认的乳腺癌进展调节剂。ECM的机械性质的变化如何转化为指导肿瘤细胞迁移和转移的生化信号仍然缺乏表征。这里,我们描述了自噬诱导丝氨酸/苏氨酸激酶ULK1和ULK2在机械转导中的新作用。我们显示ULK1/2活性抑制肌动蛋白应力纤维和粘着斑（FAs）的组装，从而阻碍细胞收缩和迁移，独立于其在自噬中的作用。机械上,我们鉴别出PXN/桩蛋白,机械传动机械的关键部件，作为ULK1/2的直接结合伴侣和底物。在S32和S119的ULK介导的PXN磷酸化减弱了PXN的同型相互作用和液-液相分离，损坏FA装配，这反过来又改变了乳腺癌细胞的机械性能及其对机械刺激的反应。ULK1/2和特性良好的PXN调节器，FAK/Src,在机械转导上具有相反的功能，并竞争相邻丝氨酸和酪氨酸残基的磷酸化。一起来看,我们的研究表明ULK1/2是PXN依赖性机械转导的重要调节因子。
