The long-term goal of this proposal is to understand the molecular and cellular mechanisms of protein kinase C and how these mechanisms are altered by cancer-associated mutations in members of this enzyme family to promote oncogenesis. Protein kinase C isozymes transduce the myriad of signals resulting from receptor-mediated hydrolysis of phospholipids, playing critical roles in diverse cellular functions The discovery in the 1980s that they are the receptors for the potent tumor promoting phorbol esters, led to the dogma that activation of protein kinase C by phorbol esters promotes tumorigenesis. However, the finding that long-term treatment with phorbol esters causes the degradation of protein kinase C opens this interpretation to question. Protein kinase C levels are aberrant in diverse cancers, and over 160 mutations in protein kinase C isozymes have been found in human cancers. However, whether protein kinase C isozymes function as tumor suppressors or oncogenes is not established. By understanding the molecular and cellular mechanisms of protein kinase C, and taking advantage of novel tools our lab has developed, we are poised to address this fundamental question. Thus, a central hypothesis driving this proposal is that protein kinase C may be a tumor suppressor, with inactivation (rather than activation, as is the dogma) of the kinase promoting oncogenic pathways.
Three Aims are proposed: 1] to advance knowledge on the molecular mechanisms of protein kinase C, 2] to understand protein kinase C signaling in cells, and 3] to examine how cancer-associated mutations in protein kinase C alter its function, testing the hypothesis that protein kinase C may be a tumor suppressor rather than oncogene.

Public Health Relevance

This research is relevant to public health because it addresses the basic molecular mechanisms of a key enzyme that controls cell signaling pathways that are often misregulated in disease. Specifically, our lab has advanced knowledge on the molecular basis of a class of enzymes, the protein kinase C family, whose members are the target of tumor promoting phorbol esters. In this proposal, we expand and apply our knowledge of the mechanisms of protein kinase C to understand how mutations in these enzymes that have been identified in human cancers promote oncogenesis, which may enable us to more effectively target this kinase in the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM043154-25A1
Application #
8577964
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Chin, Jean
Project Start
1989-12-01
Project End
2017-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
25
Fiscal Year
2013
Total Cost
$421,602
Indirect Cost
$149,601
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
Cone, Angela C; Cavin, Gabriel; Ambrosi, Cinzia et al. (2014) Protein kinase C?-mediated phosphorylation of Connexin43 gap junction channels causes movement within gap junctions followed by vesicle internalization and protein degradation. J Biol Chem 289:8781-98
Kunkel, Maya T; Newton, Alexandra C (2014) Imaging kinase activity at protein scaffolds. Methods Mol Biol 1071:129-37
Antal, Corina E; Violin, Jonathan D; Kunkel, Maya T et al. (2014) Intramolecular conformational changes optimize protein kinase C signaling. Chem Biol 21:459-69
Wu-Zhang, Alyssa X; Newton, Alexandra C (2013) Protein kinase C pharmacology: refining the toolbox. Biochem J 452:195-209
Scott, Angela M; Antal, Corina E; Newton, Alexandra C (2013) Electrostatic and hydrophobic interactions differentially tune membrane binding kinetics of the C2 domain of protein kinase C*. J Biol Chem 288:16905-15
O'Neill, Audrey K; Niederst, Matthew J; Newton, Alexandra C (2013) Suppression of survival signalling pathways by the phosphatase PHLPP. FEBS J 280:572-83
Gould, Christine M; Antal, Corina E; Reyes, Gloria et al. (2011) Active site inhibitors protect protein kinase C from dephosphorylation and stabilize its mature form. J Biol Chem 286:28922-30
Chen, Muhan; Pratt, Christopher P; Zeeman, Martha E et al. (2011) Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression. Cancer Cell 20:173-86
Newton, Alexandra C (2009) Lipid activation of protein kinases. J Lipid Res 50 Suppl:S266-71
Gould, Christine M; Kannan, Natarajan; Taylor, Susan S et al. (2009) The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase C through a conserved PXXP motif in the C-terminal tail. J Biol Chem 284:4921-35

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