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How do cells process signals from nutrients, hormones, stress and other environmental stimuli?

Our laboratory aims to understand the signal transduction mechanisms that control cellular responses including growth, proliferation, survival or differentiation.

Research in my lab currently focuses on how the mTOR signaling pathway couples cellular metabolism with growth via regulation of protein production and quality control. A central signaling pathway that controls protein synthesis involves the mammalian target of rapamycin (mTOR) protein kinase. 

mTOR responds to the presence of nutrients and growth factors such as insulin to control metabolic pathways and cellular process such as transcription and translation.  Our lab employs biochemical and cell biological techniques using mammalian cell lines and yeast to address the cellular functions of mTOR.  To understand how cellular signals affect organismal growth and metabolism, we are also using mouse knockout models to study the role of the mTOR pathway in growth, development, and metabolism of the immune system. Our research aims to exploit novel mTOR targets in protein synthesis and maturation for therapeutic development and translational application against cancer and other metabolic disorders.

What is mTOR?

mTOR stands for mammalian or mechanistic target of rapamycin. Rapamycin is a naturally occuring compound (drug) that was originally isolated from soil samples in the island of Rapa Nui (Easter Island). It was found to have immunosuppressive activity and is being developed as an anti-cancer drug. Furthermore, this drug has been shown to prolong lifespan in lower organisms and mice. Could it be the elixir of life?

In the lab, rapamycin has been instrumental in understanding the functions of mTOR. TOR in yeast was the first to be identified using this drug. In this organism, TOR controls the growth machinery in response to the presence of nutrients. This function of yeast TOR has been conserved through evolution and mTOR is now known as a central controller of growth. Since multicellular organisms rely on other environmental or extracellular inputs for growth, such as growth factors, cytokines, and hormones, mTOR can process these different inputs to control cell and organismal growth.

How does mTOR control cell growth?

mTOR is a protein kinase (enzyme) that is regulated by signals coming from nutrients (such as amino acids) and growth factors/hormones (such as insulin). It forms protein complexes by associating with other proteins. So far, there are two mTOR protein complexes (mTORC1 and mTORC2). Association with distinct partners can regulate its activity and function. mTOR, along with its partners, can also undergo modifications (eg phosphorylation) that can alter its activity. We (and other labs as well) are trying to understand how the mTOR protein complexes are regulated by nutrients and insulin. When there are sufficient growth signals, the mTOR pathway is activated; anabolic processes are augmented along with increased gene transcription, protein production to promote cell growth and proliferation. One of the main interests in our lab is to understand how mTOR couples protein production with quality control (processing or maturation) of the newly synthesized proteins.

Why is mTOR relevant for cancer and other metabolic disorders?

Cancer cells have aberrant growth and metabolism. Most of the genes that encode proteins that are part of the mTOR pathway, including mTOR itself, have been found to be mutated in a number of cancers. Mutation of these genes lead to deregulated activity of the protein product and the mTOR pathway. Increased activity of the mTOR pathway is like an "engine gone out of control". The cellular engine cranks up the fuel supply to support uncontrolled growth and proiferation. How can we stop the fuel supply? Since all living cells in our body require fuel, how can we specifically stop the fuel supply of cancer cells? These are some of the questions we address in our lab.