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Professor of PharmacologyProfessor of
Primary Office: 2-252 Bowen Science BuildingIowa City, IA 52242
Primary Office Phone: 319-384-4439
Lab: 2-240 Bowen Science BuildingIowa City, IA 52242
PhD, Biology, State University of New York at Albany, Albany, NY
Biosciences Graduate ProgramInterdisciplinary Graduate Program in Molecular and Cellular BiologyInterdisciplinary Graduate Program in NeuroscienceInterdisciplinary Graduate Program in Translational BiomedicineMedical Scientist Training Program
Protein phosphatase 2A in neuronal signal transduction Reversible phosphorylation of key proteins, such as ion channels and neurotransmitter-synthesizing enzymes, regulates synaptic transmission and other aspects of neuronal physiology and development. While the enzymes that add phosphates to proteins, protein kinases, have been studied extensively, much less is known about the equally important enzymes that catalyze the reverse reaction, protein phosphatases. My laboratory is interested in the roles of one of the major serine/threonine phosphatases, protein phosphatase 2A (PP2A) in normal and pathological brain function. PP2A is a diverse group of multi-subunit enzymes consisting of a constant catalytic (C) and scaffolding (A) subunit and a third variable, or regulatory (B) subunit. Regulatory subunits control enzymatic activity and substrate specificity and target PP2A holoenzymes to different parts of the cell. Research in the lab focuses on PP2A regulatory subunits that are highly expressed in brain, since they are likely to regulate specifically neuronal functions. One of these neuronal PP2A subunits, B' b is mutated in a human neurodegenerative disorder, spinocerebellar ataxia type 12 (SCA12), implying that this subunit is essential for neuronal survival. Current studies focus on structure/function analyses of PP2A holoenzymes, regulation of signal transduction cascades and neurotransmitter synthesis by PP2A, and restructuring of neuronal mitochondria by kinases and phosphatases. Select current projects: 1) Role of PP2A in nerve growth factor signaling and neurite outgrowth. Overexpression of the neuronal B' b subunit promotes differentiation of neuronal PC12 cells by stimulating the mitogen- activated protein kinase (MAPK) cascade. The B' b subunit, conversely, inhibits MAPK signaling, indicating that this important signal transduction cascade is regulated both positively and negatively by PP2A. Using RNA interference and pharmacological approaches, we are in the process of identifying the molecular targets of PP2A/B' b and B' b. 2) Regulation of mitochondrial function and neuronal survival. We have recently discovered a novel alternative splice variant of the neuronal B' b PP2A subunit that is mutated in the SCA12 disorder. The divergent N-terminus of B b2 targets PP2A to mitochondria to promote neuronal cell death by apoptosis. An outer mitochondrial cAMP-dependent protein kinase (PKA) holoenzyme opposes the death-inducing activity of PP2A/B b2. Using B b2 knockout mice and primary hippocampal cultures, we are identifying the physiological functions and molecular targets of outer mitochondrial PP2A and PKA. 3) Structure-function analysis of PP2A holoenzymes. Using site-directed mutagenesis and a variety of in vitro analyses, we are investigating how regulatory subunits interact with the A and C subunit to determine substrate specificity. The B' family of PP2A subunits are heavily phosphorylated in cells, and we are studying the effect of phosphorylation of specific residues on catalytic activity and subcellular localization. 4) Regulation of catecholamine biosynthesis by PP2A. We found that tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of dopamine and (nor)epinephrine, is dephosphorylated and inactivated by a neuron-specific PP2A holoenzyme containing the B' b subunit. We are exploring the regulation of PP2A/B' b activity in dopaminergic neurons with the eventual goal of developing new Parkinson's disease therapies.
Allosteric modulation of Drp1 mechanoenzyme assembly and mitochondrial fission by the variable domain.
J Biol Chem.
Age-dependent targeting of protein phosphatase 1 to Ca2+/calmodulin-dependent protein kinase II by spinophilin in mouse striatum.
Baucum II A,
PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics.
The antagonistic action of B56-containing protein phosphatase 2As and casein kinase 2 controls the phosphorylation and Gli turnover function of Daz interacting protein 1.
J Biol Chem.
A kinase anchor protein 150 (AKAP150)-associated protein kinase A limits dendritic spine density.
J Biol Chem.
Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.
Determinants for Substrate Specificity of Protein Phosphatase 2A.
:Article ID 398751 - 8 pages.
Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation.
Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties.
J Biol Chem.
Molecular determinants for PP2A substrate specificity: charged residues mediate dephosphorylation of tyrosine hydroxylase by the PP2A/B' regulatory subunit.
Date Last Modified: 06/18/2013 -
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