Signaling

While historically signaling pathways and metabolic pathways were often studied separately, it is now clear that signaling and metabolic control are intimately linked.   For example circulating growth factors through cell surface receptors activate intracellular signaling pathways, which promote the uptake of nutrients.  Inside the cell, certain bioactive nutrients and other metabolic products also function as signaling molecules that control the activity of signaling pathways and transcriptional regulators.  Many of these connections are aberrantly altered in type 2 diabetes (T2D) and cancer and one of our goals is to mechanistically define these connections and their potential as targets for therapeutic intervention.

 

Signaling & Metabolism

                    Model of how signaling and metabolism can intersect

In particular, we have a long-standing interest in the mTOR-signaling pathway.  The mTOR protein, which is a serine/threonine kinase and the target of the immunosuppressant and anti-cancer drug rapamycin, senses both intracellular nutrients and circulating growth factors, and through its assembly into at least two distinct multi-subunit complexes (called mTOR complex 1/mTORC1 and mTORC2), controls several metabolic processes critical for cancer progression and the onset of T2D.  Each complex can be defined by unique interacting proteins.  For example, mTORC1 contains ther Raptor protein while mTORC2 contains Rictor.  The mTOR complexes also have unique upstream inputs and downstream functions and part of our ongoing efforts is to define the less understood mTORC2 branch of the pathway and its key functions in metabolism and human disease.


 

mTORC2 model

Model of mTOR Complex 2 (mTORC2) signaling. 
One of the best described functions of mTORC2 is to phosphorylate the AKT kinase on a key activation site at Ser 473 located in a carboxy-terminal hydrophobic motif (HM).  Phosphorylation of AKT by mTORC2 and PDK1 (at T308) are thought to be required for full AKT activity.