Sciarretta Sebastiano, Zhai Peiyong, Maejima Yasuhiro, Del Re Dominic P, Nagarajan Narayani, Yee Derek, Liu Tong, Magnuson Mark A, Volpe Massimo, Frati Giacomo, Li Hong, Sadoshima Junichi
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; IRCCS Neuromed, Pozzilli 86077, Italy.
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
Cell Rep. 2015 Apr 7;11(1):125-36. doi: 10.1016/j.celrep.2015.03.010. Epub 2015 Apr 2.
The mTOR and Hippo pathways have recently emerged as the major signaling transduction cascades regulating organ size and cellular homeostasis. However, direct crosstalk between two pathways is yet to be determined. Here, we demonstrate that mTORC2 is a direct negative regulator of the MST1 kinase, a key component of the Hippo pathway. mTORC2 phosphorylates MST1 at serine 438 in the SARAH domain, thereby reducing its homodimerization and activity. We found that Rictor/mTORC2 preserves cardiac structure and function by restraining the activity of MST1 kinase. Cardiac-specific mTORC2 disruption through Rictor deletion leads to a marked activation of MST1 that, in turn, promotes cardiac dysfunction and dilation, impairing cardiac growth and adaptation in response to pressure overload. In conclusion, our study demonstrates the existence of a direct crosstalk between mTORC2 and MST1 that is critical for cardiac cell survival and growth.
mTOR和Hippo信号通路最近已成为调节器官大小和细胞稳态的主要信号转导级联反应。然而，两条信号通路之间的直接相互作用尚未确定。在此，我们证明mTORC2是Hippo信号通路关键组分MST1激酶的直接负调控因子。mTORC2使MST1的SARAH结构域中的丝氨酸438磷酸化，从而降低其同源二聚化和活性。我们发现，Rictor/mTORC2通过抑制MST1激酶的活性来维持心脏结构和功能。通过敲除Rictor进行心脏特异性mTORC2破坏会导致MST1的显著激活，进而促进心脏功能障碍和扩张，损害心脏生长以及对压力超负荷的适应性。总之，我们的研究证明了mTORC2与MST1之间存在直接相互作用，这对心脏细胞的存活和生长至关重要。
