American Cancer Society Professor
Molecular and Cell Biology Laboratory
Renato Dulbecco Chair
Tony Hunter, a Professor in the Molecular and Cell Biology Laboratory and Director of the Salk Institute Cancer Center, studies how cell growth and division are regulated, and how mutations in genes that control growth lead to cancer. His group has made significant contributions in the area of signal transduction, elucidating how signals that stimulate or inhibit proliferation are transmitted within a cell.
In 1979, his group discovered that phosphate can be attached to tyrosine residues in proteins. This seminal discovery opened the door to the study of tyrosine kinases and their role in signal transduction, and in cell proliferation and development, as well as to their role in cancer and other human diseases. This knowledge already has resulted in the development of selective tyrosine kinase inhibitors that provide a new approach to cancer treatment.
His current efforts are aimed at elucidating how post-translational modification of proteins by phosphorylation, ubiquitylation, and sumoylation is used to regulate cell proliferation and cell cycle checkpoint activation in response to DNA damage. His recent work has highlighted crosstalk between phosphorylation and ubiquitylation, and between sumoylation and ubiquitylation in the control of cell signaling pathways, and in particular has defined the role of SUMO-targeted E3 ubiquitin ligases, such as RNF4 family ligases, that ubiquitylate sumoylated proteins leading to their degradation. His group has also defined a role for ubiquitylation in lifespan determination in C. elegans, characterized the consequences of somatic mutations in protein kinases such as DAPK3 in carcinogenesis, and has recently developed antibody reagents for studying histidine phosphorylation.
Protein kinases are key cellular enzymes; they attach phosphates to other proteins in the cell and thereby regulate their activities. This process, which is known as phosphorylation, is reversed by a second type of enzyme that removes the phosphate. Phosphorylation therefore acts as a molecular on/off switch. The human genome encodes nearly 540 different protein kinases, making them among the most abundant and important types of gene products.
One major function of protein phosphorylation is to control cell proliferation in response to external signals. A hallmark of cancer cells is that they continue to proliferate even in the absence of external signals to grow. In many cases, this is due to genetic changes that result in a protein kinase being continuously active instead of being toggled on and off in response to signals. Kinases that add phosphate to the amino acid tyrosine in proteins are particularly important cancercausing "oncoproteins," and a number of new cancer drugs are designed to block these rogue enzymes. However, kinases that add phosphates to the amino acids serine or threonine in proteins also play roles in cancer. Recent efforts to sequence entire tumor genomes have revealed that many types of protein kinases sustain mutations in cancer, including numerous ones that were not previously known to be involved.
Hunter and his team have analyzed the consequences of mutations in some of these cancer mutant kinases in the hope that they might identify new cancer drug targets. For one kinase that phosphorylates serine and threonine, known as death-associated protein kinase 3 or DAPK3, they found that the cancer mutations actually cause a decrease in the ability of the kinase to add phosphate to proteins. This unexpected discovery suggests a new model in which DAPK3 normally acts to rein in the growth of cells, whereas in cancer cells this "suppressor" activity has been lost through inactivating mutations. Thus, DAPK3 would not be a target for inhibitor drugs. Nevertheless, other mutant kinases emerging from sequencing studies may prove to be good targets, and Hunter's group is continuing to study cancer mutant kinases in the hope that unlocking their secrets will lead to better cancer therapies.