The overall vision of our research is to gain a comprehensive understanding of the molecular mechanisms driving the function of understudied kinase PRKCQ in order to effectively target it in disease. PRKCQ encodes the protein kinase C (PKC) isozyme PKCq. The PKC family has been intensely investigated in the context of cancer since the discovery in the early 1980s that it is a receptor for the tumor-promoting phorbol esters. This led to the dogma that activation of PKC by phorbol esters promotes carcinogen-induced tumorigenesis. Nonetheless, PKC has been an elusive chemotherapeutic target despite decades of research. We recently established that, contrary to conventional thinking, PKC generally functions as a tumor suppressor, not an oncogene, thus explaining why 30+ years of clinical trials with PKC inhibitors not only failed but, in some cases, worsened patient outcome. In this proposal, we aim to combine bioinformatics, computational, biochemical, and cellular approaches to rapidly understand the molecular details of PKCq and how disease-associated mutations impact function and biology. Uncovering the function of PKCq in oncogenic signaling will inform on how to appropriately target it in cancer therapies.

Public Health Relevance

/Relevance This research is relevant to public health because it addresses the basic molecular mechanisms of how an understudied, but highly druggable and important, signaling enzyme is deregulated in disease. Our molecular understanding of how other members of this family of proteins, the protein kinase C enzymes, allowed us to reverse a dogma and show that these enzymes generally suppress cancer, rather than promoting it, explaining why inhibitors for it have failed in clinical trials for cancer. We would like to understand the mechanisms by which the understudied PRKCQ member of the family is deregulated and how deregulation contributes to pathophysiologies such as cancer.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Small Research Grants (R03)
Project #
1R03TR002914-01
Application #
9813191
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sharma, Karlie Roxanne
Project Start
2019-08-20
Project End
2020-08-19
Budget Start
2019-08-20
Budget End
2020-08-19
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093