Atypical PKC isoforms (iota/zeta) have been shown to play a critical role in regulation of various neuronal processes including, differentiation, survival and long-term potentiation. In PC-12 cells a PKCs, as well as their second messenger activator, P13 polyphosphoinositides, are required for both differentiation and survival responses. We have recently shown that aPKCs are tyrosine phosphorylated in response to nerve growth factor (NGF). ZIP/p62 and Par4 are binding proteins that regulate the localization and activation of aPKCs. Preliminary studies document an NGF receptor-regulated phosphotyrosine dependent interaction of src with sPKC. We hypothesize that tyrosine phosphorylation of atypical PKC by src moduates activity, as well as, its ability to interact with its protein regulators, Par4 and ZIP. Therefore, one specific aim is to study the mechanisms by which aPKC-iota is regulated by tyrosine phsophorylation to include regulation by NGF receptor components, p75 and TrkA, as well as, second messenger.
A second aim i s to unravel the mechanismwhereby aPKC is regulated by src kinase to include regulation of aPKC localization, signal-complex formation and interaction with protein regulators, as well as to examine the specific tyrosine residues that regulate NGF/aPKC signal-coupling. Various biochemical and functional assays will be used to define the function of src in regulation of aPKC signaling. Overall, a comprehensive set of experiments using enzyme activity assays, subcellular fractionation, coimmunoprecipitation and site-directed mutagenesis will be employed. The outcome of this work will continue to alter the conceptual framework of neurotrophic signal coupling and the role that aPKC plays in this process. These findings will contribute to further understanding of the mechanism whereby aPKC is regulated and may provide new therapeutic targets for neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS033661-04A1
Application #
2902695
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Heemskerk, Jill E
Project Start
1995-08-01
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Auburn University at Auburn
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
City
Auburn University
State
AL
Country
United States
Zip Code
36849
Seibenhener, Michael L; Wooten, Michael C (2015) Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp :e52434
Du, Yifeng; Seibenhener, Michael L; Yan, Jin et al. (2015) aPKC phosphorylation of HDAC6 results in increased deacetylation activity. PLoS One 10:e0123191
Calderilla-Barbosa, Luis; Seibenhener, M Lamar; Du, Yifeng et al. (2014) Interaction of SQSTM1 with the motor protein dynein--SQSTM1 is required for normal dynein function and trafficking. J Cell Sci 127:4052-63
Seibenhener, M Lamar; Du, Yifeng; Diaz-Meco, Maria-Theresa et al. (2013) A role for sequestosome 1/p62 in mitochondrial dynamics, import and genome integrity. Biochim Biophys Acta 1833:452-9
Seibenhener, M Lamar; Zhao, Ting; Du, Yifeng et al. (2013) Behavioral effects of SQSTM1/p62 overexpression in mice: support for a mitochondrial role in depression and anxiety. Behav Brain Res 248:94-103
Yan, Jin; Seibenhener, Michael Lamar; Calderilla-Barbosa, Luis et al. (2013) SQSTM1/p62 interacts with HDAC6 and regulates deacetylase activity. PLoS One 8:e76016
Seibenhener, Michael L; Wooten, Marie W (2012) Isolation and culture of hippocampal neurons from prenatal mice. J Vis Exp :
Du, Yifeng; Wooten, Michael C; Gearing, Marla et al. (2009) Age-associated oxidative damage to the p62 promoter: implications for Alzheimer disease. Free Radic Biol Med 46:492-501
Jadhav, Trafina; Wooten, Marie W (2009) Defining an Embedded Code for Protein Ubiquitination. J Proteomics Bioinform 2:316
Jiang, Jianxiong; Parameshwaran, Kodeeswaran; Seibenhener, M Lamar et al. (2009) AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62. Hippocampus 19:392-406

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