Abstract

This Mentored Career Development Award application outlines a program of career development and research training for the applicant. The ultimate goal of the candidate is to develop as a successful independent scientist in cancer research and signaling. The career development and research plan are designed to allow the candidate to reach this goal by provide him with the necessary theoretical and methodological aspects of signal transduction, as related to cell growth and cancer, and with the necessary tools that will enable him to successfully develop an independent research career and compete for independent funding. The Mentor's candidate, Dr. Enrique Rozengurt, is an internationally recognized expert in the field of signal transduction and growth regulation with extensive experience in cancer research. The UCLA-Department of Medicine, which is the environment where the candidate will develop his training and research, offers extraordinary opportunities for intellectual interactions amid a very supportive and exciting atmosphere for the development of young scientists. The more immediate priority of the candidate is to obtain grant support in order to continue his research and growth as a scientist. ? ? The candidate's research project aims to characterize the mechanisms regulating the translocation to different cellular compartments of a signaling molecule (protein kinase D/PKD) that binds the tumor promoters phorbol esters as well as diacylglycerols and to identify its downstream targets. PKD is a member of a new family of serine/threonine kinases implicated in the regulation of a variety of cellular functions, including DNA synthesis and cell proliferation, that is a downstream effector of novel protein kinase C. The candidate will analyze the intracellular translocation properties of protein kinase PKD in response to phorbol esters and G protein-coupled receptor mitogenic agonist employing real-time imaging of fluorescent-tagged PKD expressed in normal fibroblast and pancreatic cancer cells. For the identification of proteins interacting with PKD in the different cellular compartments, the applicant plans to use mass spectrometry and peptide mass fingerprinting. Our hypothesis is that the kinase activity of PKC regulates PKD by coordinating its catalytic activation and intracellular localization. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA097956-04
Application #
7025096
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2003-03-17
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$146,880
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Sinnett-Smith, James; Zhukova, Elena; Rey, Osvaldo et al. (2007) Protein kinase D2 potentiates MEK/ERK/RSK signaling, c-Fos accumulation and DNA synthesis induced by bombesin in Swiss 3T3 cells. J Cell Physiol 211:781-90
Kisfalvi, Krisztina; Rey, Osvaldo; Young, Steven H et al. (2007) Insulin potentiates Ca2+ signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by Gq protein-coupled receptor agonists through an mTOR-dependent pathway. Endocrinology 148:3246-57
Rey, Osvaldo; Papazyan, Romeo; Waldron, Richard T et al. (2006) The nuclear import of protein kinase D3 requires its catalytic activity. J Biol Chem 281:5149-57
Papazyan, Romeo; Rozengurt, Enrique; Rey, Osvaldo (2006) The C-terminal tail of protein kinase D2 and protein kinase D3 regulates their intracellular distribution. Biochem Biophys Res Commun 342:685-9
Yuan, Jingzhen; Rey, Osvaldo; Rozengurt, Enrique (2006) Activation of protein kinase D3 by signaling through Rac and the alpha subunits of the heterotrimeric G proteins G12 and G13. Cell Signal 18:1051-62
Rey, Osvaldo; Young, Steven H; Papazyan, Romeo et al. (2006) Requirement of the TRPC1 cation channel in the generation of transient Ca2+ oscillations by the calcium-sensing receptor. J Biol Chem 281:38730-7
Yuan, Jingzhen; Rey, Osvaldo; Rozengurt, Enrique (2005) Protein kinase D3 activation and phosphorylation by signaling through G alpha q. Biochem Biophys Res Commun 335:270-6
Rey, Osvaldo; Reeve Jr, Joseph R; Zhukova, Elena et al. (2004) G protein-coupled receptor-mediated phosphorylation of the activation loop of protein kinase D: dependence on plasma membrane translocation and protein kinase Cepsilon. J Biol Chem 279:34361-72
Waldron, Richard T; Rey, Osvaldo; Zhukova, Elena et al. (2004) Oxidative stress induces protein kinase C-mediated activation loop phosphorylation and nuclear redistribution of protein kinase D. J Biol Chem 279:27482-93
Rey, Osvaldo; Yuan, Jingzhen; Young, Steven H et al. (2003) Protein kinase C nu/protein kinase D3 nuclear localization, catalytic activation, and intracellular redistribution in response to G protein-coupled receptor agonists. J Biol Chem 278:23773-85

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