The roles of protein phosphatases in neuronal function and dysfunction are poorly understood. Protein phosphatase 2A (PP2A) is a ubiquitous and abundant enzyme with roles in most cellular processes that involve reversible Ser/'rhr phosphorylation. In neurons, PP2A dephosphorylates a staggering array of substrates include cytoskeletal proteins, receptors and ion channels, neurotransmitter-synthesizing enzymes, kinases, and transcription factors. PP2A is a trimeric holoenzyme of two core subunits (a catalytic and a scaffold subunit) complexed to a variable, regulatory subunit. The identity of the regulatory subunit determines where the PP2A holoenzyme is localized, which substrates it dephosphorylates, and how its activity is modulated by intracellular signaling. None of this has been investigated in any detail. Some variable, regulatory subunits are only expressed in brain, suggesting that brain-specific PP2A holoenzymes have unique roles in neuronal physiology and development. A trinucleotide repeat expansion in the promoter region of one of these neuron-specific subunits, B[beta], has recently been linked to spinocerebellar ataxia type 12 (SCA12). Thus, aberrant PP2A subunit expression may be a hallmark of certain human neurodegenerative disorders. In this proposal, we explore the roles of the brain regulatory subunit B[gamma] in subcellular localization of PP2A holoenzymes and developmental signal transduction cascades.
Aim 1 investigates the sequence determinants for differential subcellular localization of B subunits, and for association with the two core PP2A subunits. Proteins that interact with the B[gamma] subunit are identified in Aim 2 using yeast two-hybrid and protein purification techniques.
Aim 3 investigates the function of neuronal PP2A regulatory subunits in Ras-MAP kinase signaling and neurite outgrowth of PC12 cells and primary neurons. These studies will significantly advance our understanding of how the ubiquitous PP2A enzyme regulates specifically neuronal functions, and may lead to the development of drugs that target neuronal PP2A isoforms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043254-05
Application #
7149989
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Gwinn, Katrina
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
5
Fiscal Year
2007
Total Cost
$298,944
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Jin, Zhigang; Chung, Jin Wei; Mei, Wenyan et al. (2015) Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt. Mol Biol Cell 26:1160-73
Merrill, Ronald A; Slupe, Andrew M; Strack, Stefan (2013) N-terminal phosphorylation of protein phosphatase 2A/B?2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival. FEBS J 280:662-73
Wilson, Theodore J; Slupe, Andrew M; Strack, Stefan (2013) Cell signaling and mitochondrial dynamics: Implications for neuronal function and neurodegenerative disease. Neurobiol Dis 51:13-26
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Ulrich, Jason D; Kim, Man-Su; Houlihan, Patrick R et al. (2012) Distinct activation properties of the nuclear factor of activated T-cells (NFAT) isoforms NFATc3 and NFATc4 in neurons. J Biol Chem 287:37594-609
Strack, Stefan; Cribbs, J Thomas (2012) Allosteric modulation of Drp1 mechanoenzyme assembly and mitochondrial fission by the variable domain. J Biol Chem 287:10990-1001
Slupe, Andrew M; Merrill, Ronald A; Strack, Stefan (2011) Determinants for Substrate Specificity of Protein Phosphatase 2A. Enzyme Res 2011:398751
Dickey, Audrey S; Strack, Stefan (2011) PKA/AKAP1 and PP2A/B?2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics. J Neurosci 31:15716-26
Lu, Yuan; Zha, Xiang-ming; Kim, Eun Young et al. (2011) A kinase anchor protein 150 (AKAP150)-associated protein kinase A limits dendritic spine density. J Biol Chem 286:26496-506
Merrill, Ronald A; Dagda, Ruben K; Dickey, Audrey S et al. (2011) Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS Biol 9:e1000612

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