Sensing mechanisms that regulate cell growth
In order to survive, differentiate, and grow, cells must evaluate their energy status and oxygen availability, take inventory of their surrounding nutrients, hormones, cytokines, and growth factors, and then integrate this information to decide what the cell’s next step is. Amazingly, a signaling system has evolved that is capable of doing all of the above. The centerpiece of this pathway is the mTOR protein kinase. My laboratory has a long-standing interest in understanding the mechanism that regulate and are regulated by mTOR in the context of physiology and disease (for an overview of the mTOR pathway click here).
Over my career, my laboratory has had a long-standing interest in understanding of how activation of mTOR elicits the broad cellular reprograming that allows cells to grow and proliferate. Our discoveries have revealed multiple downstream effects of the mTOR signaling pathway. Namely, we have made significant contributions to our current understanding of mRNA processing and translation and how mTORC1 regulates these processes through its downstream effectors, S6K1 and 4EBP (for a video illustrating how mTORC1 and S6K1 regulate assembly of the translation preinitiation complex and RNA-helicase dependent selective translation click here). Our interest in mRNA biology and its contribution for mTORC1-mediated cellular reprogramming still stands. We have just published a study illustrating how mTORC1 regulates SRPK2, a new protein kinase effector in the mTOR pathway and regulator of splicing and mRNA stability, and how this phenomenon is essential for lipogenesis and cancer formation (click here for Lee et al, 2017 Cell ). Current research in this topic involves the study of mRNA post-translational modifications, their regulation and their contribution to mTORC1-driven diseases.
Beyond that, my laboratory has also made seminal contributions to the understanding of rapamycin and rapalogs effects in cell signaling and physiology (see here for details). Current efforts in the lab are aimed to identify the mechanisms of resistance developed by cancers to these drugs. A different angle of current research interest in my lab is the regulation of mTORC1 itself. Given its essential nature for proper cellular physiology, mTORC1 activity is naturally tightly regulated. Many advances have been made in the recent years exploring how amino acid availability and growth factor signaling regulate mTORC1 (for a review on this topic click here). Currently we are exploring the regulation of mTORC1 activity in response to amino acid starvation by a small GTPase protein, which we have discovered to be a key regulator of lysosome biology. We are also interested in the regulation of mTORC1 by specific metabolites and how the energetic state of the cell dictates mTORC1 activity status through the availability of specific metabolites.