In multicellular organisms, cells must be responsive to the immediate environment as well as to systemic cues of the physiological state to maintain cellular homeostasis and ensure a healthy life. This is achieved through the ability of cells to sense extracellular (e.g. growth factors, hormones, cytokines, neurotransmitters, amino acids, sugars and other metabolites) and intracellular (e.g. metabolites, energy, redox) factors. The ability to sense, integrate and adequately respond to all these signals is crucial for cells to thrive. Thus, cells have developed, through evolution, signaling networks that sense all these factors and transduce the information to allow cells to reprogram and meet the demands from the environment. These highly plastic and tightly regulated signaling systems are essential in maintaining a healthy and rapidly responsive cellular state. Consequently, deregulation of these systems is also at the core of diseases including cancer, immune disorders, metabolic diseases, neurodegeneration and many others.
From the beginning, the overall focus of the Blenis lab has been to understand how oncogenes, growth factors, GTPases and tumor promoting phorbol esters regulate cell fate of normal cells and when improperly regulated, how they contribute to carcinogenesis through the Ras/ERK-MAPK/RSK and PI3K/mTOR/S6K pathways. The foundation for these studies began with the discovery that Ras mediated signaling from tyrosine kinases and phorbol esters to Raf, ERK and RSK, and that active ERK and RSK subsequently translocated into the nucleus. These discoveries provided the foundation for how cells signal from the cell surface to the nucleus to regulate gene expression. Additionally, work from the lab defined how subtle differences in signal strength, duration and location dictate different cell fates. Recently, our work on ERK2 signaling is defining complex and novel mechanisms for regulating cancer progression, the initiation of the metastatic process and chemoresistance. As a part of this program we have identified an important role for propionate metabolism in cancer progression via the aging-associated oncometabolite methylmalonic acid.
At the same time that our lab was defining signaling from tyrosine kinases to Ras, the ERK-MAP kinase pathway and signaling into the nucleus, we also discovered that the natural product Rapamycin, when bound to its cellular receptor FKBP12, blocked activation of S6K but not ERK and RSK, by every agonist tested via another major signaling pathway downstream of PI3-kinase. These findings laid the foundation for how mitogens regulate PI3K/mTORC1/S6K1 signaling. Some recent work on mTORC1 signaling has led us to identify novel processes linking amino acid signaling to lysosome production, cellular location and mTORC1 activation. The role of essential fatty acids and mTORC1 regulation is also being investigated. Our recent work has identified new downstream effectors of mTORC1 and has led us to define new mechanisms for mTORC1 regulation of metabolism. Finally, we have made several contributions to how mTORC1 signaling regulates multiple steps of the Central Dogma, including transcription, pre-mRNA splicing, mRNA modifications and translational control. Our lab continues to define how these core signaling pathways are regulated and how they signal to promote the cellular reprogramming required to maintain homeostasis and their role in disease when improperly regulated. Our discoveries and approaches have required us to diversify the contexts in which we ask these questions and therefore we work on model systems ranging from cancer cell lines, primary cell cultures, organoids, mouse models as well as working with clinicians and clinician scientists to translate our findings. We hope that a better understanding of the mechanisms of regulation, and the consequences of perturbing these signaling cascades in different contexts, will allow us to find new and improved therapeutic targets for the leading causes of death in the developed world, such as cancer.
Our current research is centered on the following topics
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