The Small GTPase Complex Coordinately Regulates MTORC1 Signaling Pathway

The growth and proliferation of each cell in the multicellular organisms is affected by various factors.Firstly,as one of the numerous cells in the organism,the cell has to obey the commands which the organism issued based on the distribution of nutrients throughout the body.Secondly,the internal nutrients and energy are the basis of cell growth and development.So,to coordinate these internal and external factors,cells evolved a complicated cell signaling network.mTORC1 is an important one of this network.mTORC1 is a central sensor of signals and is a regulation center in cells.After sensing the cellular signals,like growth factors,the intracellular nutrients,energy,stress and et al,mTORC1 regulates many life activities in cells,such as protein translation,ribosome biogenesis,the function of mitochondria,cell proliferation and autophagy,by delivering these signals to the downstream proteins.Serving as the upstream of mTORC1,Rags heterodimer and Rheb,which past researches prefer to regard as two independent components,transduce different signals.Although both Rags heterodimer and Rheb binding mTORC1 is required for the full activation of the latter,it is still unclear how Rags and Rheb cooperate.In this article,our research found that Rheb can interact with RagC.And the interaction is regulated by amino acids.Further study showed that p62/SQSTM1 is a new binding partner of Rheb and mediates the interaction of Rheb and RagC.And our data shows that the binding of p62/SQSTM1 and Rheb might be unaffected by two known signals,amino acids and growth factors,that could affect the activity of mTORC1.Furthermore,the oligomerization of p62/SQSTM1 doesn't have effect on the interaction of Rheb and RagC.It is inconsistent with the early hypothesis of other researchers.Additionally,a natural isoform of p62/SQSTM1 named isoform 2 misses the PB1 domain which is related to the oligomerization.And isoform 2 could significantly increase the interaction of Rheb and RagC as well as the activity of mTORC1.The study expands the understanding of p62/SQSTM1,especially isoform 2 and the activation of mTORC1 signaling pathway,which could provide new ideas for future researches.