Banyuhay Serrano

Apoptosis or programmed cell death is a conserved and tightly-regulated cellular pathway that enables organisms to undergo normal development, achieve homeostasis and protect themselves from cells that are no longer useful or are potentially harmful. Dysfunctions in apoptosis have been linked to a wide variety of proliferative and degenerative diseases, like cancer and Alzheimer’s disease. Unfortunately, suitable and effective caspases-directed therapies have yet to be developed. At the heart of this fundamental pathway are caspases (cysteine aspartate proteases), which work in concert with other apoptosis-related proteins to faithfully execute the intricate cascade of events leading to the cell’s demise. The long list of diseases associated with caspases indicates the severe consequences of their improper or lack of regulation. Thus, caspases are considered to be attractive drug targets which, when properly harnessed can lead to effective therapeutics for apoptosis-related diseases.

In order to exploit these powerful enzymes, it is necessary to understand how they are controlled at various checkpoints in the cell. One common but intriguing control mechanism is phosphorylation of caspases by kinases. The battle between caspases and kinases can tip the scale towards cell death or survival; however the molecular basis of regulation by phosphorylation of caspases, particularly of caspase-9, is vastly understudied. We are most interested in studying how phosphorylation blocks caspase-9 function as a result of conformational changes. At present we have uncovered the molecular basis for the action of two of the most important kinases, PKA and c-Abl.

To date, our work has successfully revealed the molecular details of two mechanisms by which phosphorylation regulates caspase-9. Given that caspase-9 is more extensively phosphorylated than any other caspase, understanding the wide variety of mechanisms of phosphorylation-mediated control of caspase-9 also provides critical insights across the caspase family. These molecular details of phosphoregulation will certainly contribute to the next generation of caspases-directed therapeutics and also has important implication for caspases-kinase co-therapies.