Spatial organization of the mTOR Complex 2 regulates lipid metabolism
Amelia Luciano | Guertin Lab | American Cancer Society Postdoctoral Fellowship
The Hallmarks of Cancer are specific abilities that many cancer cells acquire to grow uncontrollably. One of these is the ability to produce fats, or lipids, from sugar taken up from outside the cell. This is called lipogenesis. Only liver and fat cells normally undergo lipogenesis, but many types of cancer are more aggressive after acquiring the ability to produce their own fats. These fats are used to make new cell parts, activate genes, and signal to other cells to grow and divide. The mTORC2, an energy sensing signaling protein complex, is required for lipogenesis in normal cells and highly activated in cancer cells. It is plausible that mTORC2 is also required for lipid formation in cancer cells, but this hypothesis has not been tested. Our lab’s data indicates that two enzymes involved in this pathway are activated by a signaling molecule, called Akt, downstream of mTORC2. Preliminary data in cancer cells demonstrates that signaling to these enzymes requires both mTORC2 and Akt. I hypothesize that Akt requires mTORC2 activation to signal to its lipogenic substrates, because these substrates are located together at a signaling hub within the cell. Therefore, I take a two-step approach to examine the interactions of these proteins within the cell. First, I will identify the entire set of proteins that interact with mTORC2 during its activation using a state-of-the-art technology called proximity labeling. This technique will likely yield new information about the mTORC2 activation pathway which is currently poorly understood despite its upregulation in many types of cancer. Next, I will use classic cell biology and biochemistry to examine where in the cell Akt interacts with these enzymes and if this localization is necessary and sufficient for their activation. This proposal has the potential to identify new modes of mTORC2 activation and new interactors between the proteins in this lipogenic pathway. Currently, there are mTOR inhibitors which target mTORC2 and mTORC1, but these have many off target effects and are poorly tolerated by patients. This mechanistic project will identify new protein interactors for mTORC2 to place us one step closer to creating a novel mTORC2 specific drug.
