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 sought to understand 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. This has led to several seminal discoveries including how mTORC1 regulates SRPK2 to promote cancer formation by enhancing de novo lipogenesis through regulating mRNA splicing and stability of genes involved in lipid synthesis (Lee et al., Cell. 2017; Cho et al., Molecular Cell. In press). Research efforts have also been extended to study mRNA post-translational modifications, their regulation, and their contribution to mTORC1-driven tumorigenesis (Cho et al., Molecular Cell. 2021). Another area of intense focus in my lab is exploring how mTORC1 senses nutrient availability, a process that is essential for coordinating normal cellular physiology and also implicated in cancer initiation and progression. In recent years we have elucidated the mechanisms through which amino acid starvation induces significant reorganization in the distribution and abundance of lysosomes, thereby directly modulating mTORC1 activation (Mutvei et al., Nature Communications, 2020). We are also currently exploring the role of other nutrients and metabolites, with a particular focus on dietary essential omega-6 and omega-3 polyunsaturated fatty acids (PUFAs).
Moreover, we are actively characterizing how mTORC1 signaling converges on the activity and localization of glycogen synthase kinase 3 (GSK3) – one of the ‘busiest’ kinases in cells- and how this dictates metabolic dependencies across different cancer types (He, et al., Science Advances, 2022).
Finally, 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 at establishing cancer cell lines that are resistant to first, second and third generation mTOR inhibitors, and extensively characterizing them at the genetic, proteomic and metabolic level to identify the mechanisms of resistance.
