Pharmacology

Stefan Strack, PhD

Portrait

Professor of Pharmacology
Professor of Pathology

Contact Information

Primary Office: 2-452 Bowen Science Building
Iowa City, IA 52242
Primary Office Phone: 319-384-4439

Lab: 2-400 Bowen Science Building
Iowa City, IA 52242
Phone: 319-384-4447

Email: stefan-strack@uiowa.edu

Education

MS, Computer Science, State University of New York at Albany, Albany, NY
PhD, Biology, State University of New York at Albany, Albany, NY

Fellowship, Deutscher Academischer Austausch Dienst (DAAD) Fellowship, Wurzburg-Albany Exchange Program
Fellowship, Deutsche Studienstiftung for Academic Excellence
Fellowship, Teaching Fellowship, Stat University of New York at Albany, Albany, NY
Fellowship, Postdoctoral Fellowship, Morphology/Pharmacology, Pharmaceutical Manufacturers Assoc.

Education/Training Program Affiliations

Biosciences Graduate Program
Interdisciplinary Graduate Program in Molecular and Cellular Biology
Interdisciplinary Graduate Program in Neuroscience
Interdisciplinary Graduate Program in Translational Biomedicine
Medical Scientist Training Program

Research Summary

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.

All Publications

Merrill R, Strack S.  Mitochondria: A kinase anchoring protein 1: a signaling platform for mitochondrial form and function.  Int J Biochem Cell Biol.  2014. 48:92-96.
[Link]

Wilson T, Slupe A, Strack S.  Cell signaling and mitochondrial dynamics: Implications for neuronal function and neurodegenerative disease..  Neurobiology of disease.  2013 March. 51:13-26.
[PubMed]

Slupe A, Merrill R, Flippo K, Lobas M, Houtman J, Strack S.  A calcineurin docking motif (LxVP) in dynamin-related protein 1 contributes to mitochondrial fragmentation and ischemic neuronal injury.  J Biol Chem.  2013. 288(17):12353-12365.
[Link]

Strack S, Wilson T, Cribbs J.  Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules.  J Cell Biol.  2013. 201:1037-1051.
[Link]

Merrill R, Slupe A, Strack S.  N-terminal phosphorylation of protein phosphatase 2A/Bbeta2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival..  The FEBS journal.  2013 January. 280(2):662-73.
[PubMed]

Joiner M, Koval O, Li J, He B, Allamargot C, Gao Z, Luczak E, Hall D, Fink B, Chen B, Yang J, Moore S, Scholz T, Strack S, Mohler P, Sivitz W, Song L, Anderson M.  CaMKII determines mitochondrial stress responses in heart..  Nature.  2012 November. 491(7423):269-73.
[PubMed]

Strack S, Cribbs J.  Allosteric modulation of Drp1 mechanoenzyme assembly and mitochondrial fission by the variable domain..  The Journal of biological chemistry.  2012 March. 287(14):10990-1001.
[PubMed]

Baucum II A, Strack S, Colbran R.  Age-dependent targeting of protein phosphatase 1 to Ca2+/calmodulin-dependent protein kinase II by spinophilin in mouse striatum.  PLoS One.  2012. 7(2):e81554.

Oberg E, Nifoussi S, Gingras A, Strack S.  Selective proteasomal degradation of the B'beta subunit of protein phosphatase 2A by the E3 ubiquitin ligase adaptor Kelch-like 15..  The Journal of biological chemistry.  2012. 287(52):43378-89.
[PubMed]

Dagda R, Gusdon A, Pien I, Strack S, Green S, Li C, Van Houten B, Cherra S, Chu C.  Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease..  Cell death and differentiation.  2011 December. 18(12):1914-23.
[PubMed]

Dickey A, Strack S.  PKA/AKAP1 and PP2A/beta2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics..  The Journal of neuroscience : the official journal of the Society for Neuroscience.  2011 November. 31(44):15716-26.
[PubMed]

Jin Z, Mei W, Strack S, Jia J, Yang J.  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..  The Journal of biological chemistry.  2011 October. 286(42):36171-9.
[PubMed]

Lu Y, Zha X, Kim E, Schachtele S, Dailey M, Hall D, Strack S, Green S, Hoffman D, Hell J.  A kinase anchor protein 150 (AKAP150)-associated protein kinase A limits dendritic spine density..  The Journal of biological chemistry.  2011 July. 286(30):26496-506.
[PubMed]

Merrill R, Dagda R, Dickey A, Cribbs J, Green S, Usachev Y, Strack S.  Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1..  PLoS biology.  2011 April. 9(4):e1000612.
[PubMed]

Slupe A, Merrill R, Strack S.  Determinants for Substrate Specificity of Protein Phosphatase 2A.  Enzyme research.  2011. 2011:Article ID 398751.
[PubMed]

Merrill R, Slupe A, Strack S.  Spinocerebellar Ataxia type 12 (SCA12): clinical features and pathogenic mechanisms. In: Spinocerebellar Ataxias.  2011. 

Kranias G, Watt L, Carpenter H, Holst J, Ludowyke R, Strack S, Sim A, Verrills N.  Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation..  Cellular signalling.  2010 December. 22(12):1882-90.
[PubMed]

Bui M, Gilady S, Fitzsimmons R, Benson M, Lynes E, Gesson K, Alto N, Strack S, Scott J, Simmen T.  Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties..  The Journal of biological chemistry.  2010 October. 285(41):31590-602.
[PubMed]

Saraf A, Oberg E, Strack S.  Molecular determinants for PP2A substrate specificity: charged residues mediate dephosphorylation of tyrosine hydroxylase by the PP2A/B' regulatory subunit..  Biochemistry.  2010 February. 49(5):986-95.
[PubMed]

Jinsmaa Y, Florang V, Rees J, Anderson D, Strack S, Doorn J.  Products of oxidative stress inhibit aldehyde oxidation and reduction pathways in dopamine catabolism yielding elevated levels of a reactive intermediate..  Chemical research in toxicology.  2009 May. 22(5):835-41.
[PubMed]

Jin Z, Shi J, Saraf A, Mei W, Zhu G, Strack S, Yang J.  The 48-kDa alternative translation isoform of PP2A:B56epsilon is required for Wnt signaling during midbrain-hindbrain boundary formation..  The Journal of biological chemistry.  2009 March. 284(11):7190-200.
[PubMed]

Van Kanegan M, Strack S.  The protein phosphatase 2A regulatory subunits B'beta and B'delta mediate sustained TrkA neurotrophin receptor autophosphorylation and neuronal differentiation..  Molecular and cellular biology.  2009 February. 29(3):662-74.
[PubMed]

Cribbs J, Strack S.  Functional characterization of phosphorylation sites in dynamin-related protein 1.  Methods in enzymology.  2009. 457:231-53.
[PubMed]

Dagda R, Merrill R, Cribbs J, Chen Y, Hell J, Usachev Y, Strack S.  The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission..  The Journal of biological chemistry.  2008 December. 283(52):36241-8.
[PubMed]

Schnizler K, Shutov L, Van Kanegan M, Merrill M, Nichols B, McKnight G, Strack S, Hell J, Usachev Y.  Protein kinase A anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons..  The Journal of neuroscience : the official journal of the Society for Neuroscience.  2008 May. 28(19):4904-17.
[PubMed]

Strack S, Hell J.  Postsynaptic targeting of protein kinases and phosphatases.  Springer.  2008. 

Cribbs J, Strack S.  Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death..  EMBO reports.  2007 October. 8(10):939-44.
[PubMed]

Merrill R, Strack S.  Protein kinases and phosphatases.  Higher Education Press.  2007. 

Saraf A, Virshup D, Strack S.  Differential expression of the B'beta regulatory subunit of protein phosphatase 2A modulates tyrosine hydroxylase phosphorylation and catecholamine synthesis..  The Journal of biological chemistry.  2007 January. 282(1):573-80.
[PubMed]

Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu J, Strack S, Jeffrey P, Shi Y.  Structure of the protein phosphatase 2A holoenzyme..  Cell.  2006 December. 127(6):1239-51.
[PubMed]

Xing Y, Xu Y, Chen Y, Jeffrey P, Chao Y, Lin Z, Li Z, Strack S, Stock J, Shi Y.  Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins..  Cell.  2006 October. 127(2):341-53.
[PubMed]

Hall D, Feekes J, Arachchige Don A, Shi M, Hamid J, Chen L, Strack S, Zamponi G, Horne M, Hell J.  Binding of protein phosphatase 2A to the L-type calcium channel Cav1.2 next to Ser1928, its main PKA site, is critical for Ser1928 dephosphorylation..  Biochemistry.  2006 March. 45(10):3448-59.
[PubMed]

Holmes S, O'Hearn E, Cortez-Apreza N, Pletnikova O, Troncoso J, Strack S, Margolis R.  Spinocerebellar ataxia type 12.  Elsevier-Academic Press.  2006. 

Adams D, Coffee R, Zhang H, Pelech S, Strack S, Wadzinski B.  Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes..  The Journal of biological chemistry.  2005 December. 280(52):42644-54.
[PubMed]

Van Kanegan M, Adams D, Wadzinski B, Strack S.  Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt..  The Journal of biological chemistry.  2005 October. 280(43):36029-36.
[PubMed]

Dagda R, Barwacz C, Cribbs J, Strack S.  Unfolding-resistant translocase targeting: a novel mechanism for outer mitochondrial membrane localization exemplified by the Bbeta2 regulatory subunit of protein phosphatase 2A..  The Journal of biological chemistry.  2005 July. 280(29):27375-82.
[PubMed]

Merrill M, Chen Y, Strack S, Hell J.  Activity-driven postsynaptic translocation of CaMKII.  Trends in Pharmacol Sci.  2005. 26(12):645-53.
[PubMed]

Merrill M, Chen Y, Strack S, Hell J.  Activity-driven postsynaptic translocation of CaMKII.  Trends Pharmacol Sci.  2005. 26:645-653.

Strack S, Cribbs J, Gomez L.  Critical role for protein phosphatase 2A heterotrimers in mammalian cell survival..  The Journal of biological chemistry.  2004 November. 279(46):47732-9.
[PubMed]

Dagda R, Zaucha J, Wadzinski B, Strack S.  A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis..  The Journal of biological chemistry.  2003 July. 278(27):24976-85.
[PubMed]

Strack S.  Overexpression of the protein phosphatase 2A regulatory subunit Bgamma promotes neuronal differentiation by activating the MAP kinase (MAPK) cascade..  The Journal of biological chemistry.  2002 November. 277(44):41525-32.
[PubMed]

Strack S, Ruediger R, Walter G, Dagda R, Barwacz C, Cribbs J.  Protein phosphatase 2A holoenzyme assembly: identification of contacts between B-family regulatory and scaffolding A subunits..  The Journal of biological chemistry.  2002 June. 277(23):20750-5.
[PubMed]

Chen H, Otmakhov N, Strack S, Colbran R, Lisman J.  Is persistent activity of calcium/calmodulin-dependent kinase required for the maintenance of LTP?.  Journal of neurophysiology.  2001 April. 85(4):1368-76.
[PubMed]

Strack S, Robison A, Bass M, Colbran R.  Association of calcium/calmodulin-dependent kinase II with developmentally regulated splice variants of the postsynaptic density protein densin-180..  The Journal of biological chemistry.  2000 August. 275(33):25061-4.
[PubMed]

Strack S, McNeill R, Colbran R.  Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor..  The Journal of biological chemistry.  2000 August. 275(31):23798-806.
[PubMed]

Brigham K, Lane K, Meyrick B, Stecenko A, Strack S, Cannon D, Caudill M, Canonico A.  Transfection of nasal mucosa with a normal alpha1-antitrypsin gene in alpha1-antitrypsin-deficient subjects: comparison with protein therapy..  Human gene therapy.  2000 May. 11(7):1023-32.
[PubMed]

MacMillan L, Bass M, Cheng N, Howard E, Tamura M, Strack S, Wadzinski B, Colbran R.  Brain actin-associated protein phosphatase 1 holoenzymes containing spinophilin, neurabin, and selected catalytic subunit isoforms..  The Journal of biological chemistry.  1999 December. 274(50):35845-54.
[PubMed]

Strack S, Chang D, Zaucha J, Colbran R, Wadzinski B.  Cloning and characterization of B delta, a novel regulatory subunit of protein phosphatase 2A..  FEBS letters.  1999 November. 460(3):462-6.
[PubMed]

Strack S, Kini S, Ebner F, Wadzinski B, Colbran R.  Differential cellular and subcellular localization of protein phosphatase 1 isoforms in brain..  The Journal of comparative neurology.  1999 October. 413(3):373-84.
[PubMed]

Strack S, Colbran R.  Autophosphorylation-dependent targeting of calcium/ calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl- D-aspartate receptor..  The Journal of biological chemistry.  1998 August. 273(33):20689-92.
[PubMed]

Strack S, Zaucha J, Ebner F, Colbran R, Wadzinski B.  Brain protein phosphatase 2A: developmental regulation and distinct cellular and subcellular localization by B subunits..  The Journal of comparative neurology.  1998 March. 392(4):515-27.
[PubMed]

Kloeker S, Bryant J, Strack S, Colbran R, Wadzinski B.  Carboxymethylation of nuclear protein serine/threonine phosphatase X..  The Biochemical journal.  1997 October. 327 ( Pt 2):481-6.
[PubMed]

Strack S, Westphal R, Colbran R, Ebner F, Wadzinski B.  Protein serine/threonine phosphatase 1 and 2A associate with and dephosphorylate neurofilaments..  Brain research. Molecular brain research.  1997 October. 49(1-2):15-28.
[PubMed]

Colbran R, Bass M, McNeill R, Bollen M, Zhao S, Wadzinski B, Strack S.  Association of brain protein phosphatase 1 with cytoskeletal targeting/regulatory subunits..  Journal of neurochemistry.  1997 September. 69(3):920-9.
[PubMed]

Strack S, Barban M, Wadzinski B, Colbran R.  Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A..  Journal of neurochemistry.  1997 May. 68(5):2119-28.
[PubMed]

Strack S, Choi S, Lovinger D, Colbran R.  Translocation of autophosphorylated calcium/calmodulin-dependent protein kinase II to the postsynaptic density..  The Journal of biological chemistry.  1997 May. 272(21):13467-70.
[PubMed]

Strack S, Wadzinski B, Ebner F.  Localization of the calcium/calmodulin-dependent protein phosphatase, calcineurin, in the hindbrain and spinal cord of the rat..  The Journal of comparative neurology.  1996 November. 375(1):66-76.
[PubMed]

Strack S, Jacklet J.  Antiserum to an eye-specific protein identifies photoreceptor and circadian pacemaker neuron projections in Aplysia..  Journal of neurobiology.  1993 May. 24(5):552-70.
[PubMed]

Lacroix L, Strack S, Olson L, Jacklet J.  Axons of circadian pacemaker neurons in the eye of Bulla project to the central nervous system and the contralateral eye.  Comp Biochem Physiol.  1991. 98A:383-391.

Siwicki K, Strack S, Rosbash M, Hall J, Jacklet J.  An antibody to the Drosophila period protein recognizes circadian pacemaker neurons in Aplysia and Bulla..  Neuron.  1989 July. 3(1):51-8.
[PubMed]

Balaban S, Strack S.  LOGSTER - an object-oriented system for knowledge representation.  Elsevier.  1988. 3:210-219.

Date Last Modified: 06/07/2014 - 21:56:23