PDF(Pubmed)
Abstract：
The Hippo pathway is an evolutionarily conserved developmental pathway that controls organ size by integrating diverse regulatory inputs, including actomyosin-mediated cytoskeletal tension. Despite established connections between the actomyosin cytoskeleton and the Hippo pathway, the upstream regulation of actomyosin in the Hippo pathway is less defined. Here, we identify the phosphoinositide-3-phosphatase Myotubularin (Mtm) as a novel upstream regulator of actomyosin that functions synergistically with the Hippo pathway during growth control. Mechanistically, Mtm regulates membrane phospholipid PI(3)P dynamics, which, in turn, modulates actomyosin activity through Rab11-mediated vesicular trafficking. We reveal PI(3)P dynamics as a novel mode of upstream regulation of actomyosin and establish Rab11-mediated vesicular trafficking as a functional link between membrane lipid dynamics and actomyosin activation in the context of growth control. Our study also shows that MTMR2, the human counterpart of Drosophila Mtm, has conserved functions in regulating actomyosin activity and tissue growth, providing new insights into the molecular basis of MTMR2-related peripheral nerve myelination and human disorders.
摘要：
Hippo途径是一种进化上保守的发育途径，通过整合不同的调控输入来控制器官大小，包括肌动球蛋白介导的细胞骨架张力。尽管在肌动球蛋白细胞骨架和Hippo途径之间建立了联系，河马途径中肌动球蛋白的上游调节定义较少。这里,我们确定了磷酸肌醇-3-磷酸酶Myotubularin（Mtm）是一种新型的肌动球蛋白上游调节因子，在生长控制过程中与Hippo途径协同作用。机械上,Mtm调节膜磷脂PI(3)P动力学，which,反过来,通过Rab11介导的囊泡运输调节肌动球蛋白活性。我们揭示了PI（3）P动力学是肌动球蛋白上游调节的新模式，并在生长控制的背景下将Rab11介导的囊泡运输确立为膜脂质动力学与肌动球蛋白活化之间的功能联系。我们的研究还表明，果蝇Mtm的人类对应物MTMR2，在调节肌动球蛋白活性和组织生长方面具有保守的功能，为MTMR2相关周围神经髓鞘形成和人类疾病的分子基础提供了新的见解。
