MERIT Award Recipient: John Blenis, Ph.D.
Mitogenic and Oncogenic Regulation of ERK/RSK Signaling
The evolutionarily conserved Ras protein plays an essential role in regulating diverse biological processes such as cell survival, cell proliferation and cell migration. The importance of this protein in the proper regulation of these biological processes is underscored by the demonstration that 30% of human cancers have activating Ras mutations and another 20% have mutations in other regulatory proteins that result in aberrant Ras activity. Furthermore, several proto-oncogenes are known to be regulated downstream of Ras. Two major effectors of Ras signaling include the ERK and RSK families of protein kinases. ERK and RSK play a major role in sending signals from Ras to many of its biological targets and thus are critical molecular targets for cancer therapy.
Current research in the Blenis Laboratory is aimed at further understanding the molecular details of how the RSK protein kinase family contributes to Ras function in normal cells as well as in cells transformed by various oncogenic proteins. Recent work from the lab demonstrates a role for RSK in cell survival signaling via the phosphorylation and inhibition of the pro-apoptotic protein BAD. In addition to preventing cell death, RSK directly promotes cell survival by regulating the expression of pro-survival proteins. They have also established a role for RSK in regulating the function of the proto-oncoprotein c-Fos and its family members. Proposed work will test the hypothesis that RSK regulates cell migration and nucleo-cytoplasmic transport via phosphorylation of newly identified targets. Ultimately, the Blenis laboratory hopes to understand how RSK is regulated, how RSK contributes to cancer when improperly activated, and how to prevent uncontrolled signaling by RSK. The long-term goal is to develop screening assays to identify inhibitors of RSK and downstream RSK targets. These studies will further the current understanding of how Ras promotes the survival, growth, proliferation, and metastatic potential of human cancer cells and ultimately lead to drugs to inhibit these deadly features of cancer.