The long term goal of our research is to understand the molecular mechanisms driving the propagation and termination of protein kinase C (PKC) signaling in response to agonists in cells. PKC has been in the spotlight since the discovery three decades ago that it is activated by the lipid second messenger, diacylglycerol. Despite PKC's enduring stage presence and tremendous advances in understanding the enzymology and regulation of this key protein, understanding the function of PKC in biology is still under intense pursuit. We have previously focused on understanding the molecular mechanisms of PKC as a first step in understanding how this key protein functions in the cell. Under the auspices of the MERIT Award, we ventured away from our biochemical studies and dove into the cell, asking the guestion: what does protein kinase C do in the cell? We developed novel genetically-encoded reporters that allowed us to simultaneously visualize PKC activity and second messenger production in real time in live cells. In the next funding period, we propose to take this new technology to the next level and develop reporters that will allow us to simultaneously image two or more kinase activities at in the same cell. This will allow us to examine the interplay between different signaling pathways, feedback mechanisms, and identify regulatory inputs that our previous biochemical studies could not address. The three major questions we ask are: 1] how does PKC impact other signaling pathways? 2] how do phosphatases control signal amplitude and signal termination? and 3] how are atypical PKC isozymes regulated in cells? Thus, in the next funding period, we aim to understand the cellular mechanisms of signal propagation, signal termination, and signal cross-talk using novel fluorescence technologies to 'spy'on cell signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM043154-24
Application #
8225203
Study Section
Special Emphasis Panel (NSS)
Program Officer
Chin, Jean
Project Start
1989-12-01
Project End
2013-08-31
Budget Start
2012-03-01
Budget End
2013-08-31
Support Year
24
Fiscal Year
2012
Total Cost
$410,453
Indirect Cost
$140,369
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
Alfonso, Stephanie I; Callender, Julia A; Hooli, Basavaraj et al. (2016) Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease. Sci Signal 9:ra47
Dowling, Catríona M; Phelan, James; Callender, Julia A et al. (2016) Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival. Oncotarget 7:20919-33
Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73
Antal, Corina E; Hudson, Andrew M; Kang, Emily et al. (2015) Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor. Cell 160:489-502
Antal, Corina E; Callender, Julia A; Kornev, Alexandr P et al. (2015) Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII. Cell Rep 12:1252-60
Cone, Angela C; Cavin, Gabriel; Ambrosi, Cinzia et al. (2014) Protein kinase Cδ-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
Antal, Corina E; Newton, Alexandra C (2014) Tuning the signalling output of protein kinase C. Biochem Soc Trans 42:1477-83
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
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

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