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Brian E. Wadzinski, Ph.D.
Associate Professor of Pharmacology
VICC Member
Researcher
Contact Information:
Vanderbilt University Medical Center
724 Robinson Research Building
Nashville, TN 37232-6600
615-343-2080
Research Specialty
Structure, function, and regulation of protein serine/threonine phosphatases
Research Description
The integrated actions of both protein kinases and phosphatases govern the phosphorylation state of key intracellular proteins which are crucial for normal cellular function. Although less attention has been given to the protein serine/threonine phosphatases than to the serine/threonine kinases, it is nonetheless clear that this group of proteins plays an integral role in the control of cell growth and differentiation. Our overall research program is the study of cellular protein serine/threonine phosphatases (PPs); however, our studies have focused on PP2A-like enzymes. This family of holoenzymes has been implicated in many facets of cellular function including regulation of metabolic enzymes, cell-surface receptors, cytosolic protein kinases, and transcription factors. Moreover, PP2A itself is regulated in many ways which include association with regulatory subunits, activation or inactivation by associated proteins, and post-translational modifications. We are using multiple complementary approaches including biochemical, immunological, and molecular biology techniques to determine the structure, function, cellular localization, and regulation of PP2A-like enzymes. Particular emphasis has been placed on studying PP2A multi-protein complexes as a first step towards understanding in molecular detail the way phosphorylation/dephosphorylation reactions control cell signalling pathways. Our studies have revealed the existence of protein kinase/PP2A signaling modules as a new paradigm for the control of various intracellular signaling cascades.
Publications
- McConnell, JL, Wadzinski, BE Targeting protein serine/threonine phosphatases for drug development. Mol Pharmacol, 75(6), 1249-61, 2009.
- Guo, S, Burnette, R, Zhao, L, Vanderford, NL, Poitout, V, Hagman, DK, Henderson, E, Ozcan, S, Wadzinski, BE, Stein, R The stability and transactivation potential of the mammalian MafA transcription factor are regulated by serine 65 phosphorylation. J Biol Chem, 284(2), 759-65, 2009.
- Wang, N, Leung, HT, Pak, WL, Carl, YT, Wadzinski, BE, Shieh, BH Role of protein phosphatase 2A in regulating the visual signaling in Drosophila. J Neurosci, 28(6), 1444-51, 2008.
- McConnell, JL, Gomez, RJ, McCorvey, LR, Law, BK, Wadzinski, BE Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase activity in the ATM/ATR signaling pathway. Oncogene, 26(41), 6021-30, 2007.
- Wegner, AM, McConnell, JL, Blakely, RD, Wadzinski, BE An Automated Fluorescence-Based Method for Continuous Assay of PP2A Activity. Methods Mol Biol, 36561-70, 2006.
- Khoo, MS, Li, J, Singh, MV, Yang, Y, Kannankeril, P, Wu, Y, Grueter, CE, Guan, X, Oddis, CV, Zhang, R, Mendes, L, Ni, G, Madu, EC, Yang, J, Bass, M, Gomez, RJ, Wadzinski, BE, Olson, EN, Colbran, RJ, Anderson, ME Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy. Circulation, 114(13), 1352-9, 2006.
- Bridges, D, MacDonald, JA, Wadzinski, B, Moorhead, GB Identification and characterization of D-AKAP1 as a major adipocyte PKA and PP1 binding protein. Biochem Biophys Res Commun, 346(1), 351-7, 2006.
- Codreanu, SG, Adams, DG, Dawson, ES, Wadzinski, BE, Liebler, DC Inhibition of protein phosphatase 2A activity by selective electrophile alkylation damage. Biochemistry, 45(33), 10020-9, 2006.
- Adams, DG, Wadzinski, BE Isolation and Characterization of PP2A Holoenzymes Containing FLAG-Tagged B Subunits. Methods Mol Biol, 365101-12, 2006.
- Veluthakal, R, Wadzinski, BE, Kowluru, A Localization of a nuclear serine/threonine protein phosphatase in insulin-secreting INS-1 cells: potential regulation by IL-1beta. Apoptosis, 11(8), 1401-11, 2006.
- Veluthakal, R, Wadzinski, BE, Kowluru, A Localization of a nuclear serine/threonine protein phosphatase in insulin-secreting INS-1 cells: potential regulation by IL-1beta. Apoptosis, 2006.
- Fritz, A, Brayer, KJ, McCormick, N, Adams, DG, Wadzinski, BE, Vaillancourt, RR Phosphorylation of serine 526 is required for MEKK3 activity, and association with 14-3-3 blocks dephosphorylation. J Biol Chem, 281(10), 6236-45, 2006.
- Van Kanegan, MJ, Adams, DG, Wadzinski, BE, Strack, S Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt. J Biol Chem, 280(43), 36029-36, 2005.
- Zhang, X, Ozawa, Y, Lee, H, Wen, YD, Tan, TH, Wadzinski, BE, Seto, E Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev, 19(7), 827-39, 2005.
- Kray, AE, Carter, RS, Pennington, KN, Gomez, RJ, Sanders, LE, Llanes, JM, Khan, WN, Ballard, DW, Wadzinski, BE Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A. J Biol Chem, 280(43), 35974-82, 2005.
- Adams, DG, Coffee, RL, Zhang, H, Pelech, S, Strack, S, Wadzinski, BE Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes. J Biol Chem, 280(52), 42644-54, 2005.
- Garriga, J, Jayaraman, AL, Limón, A, Jayadeva, G, Sotillo, E, Truongcao, M, Patsialou, A, Wadzinski, BE, Graña, X A dynamic equilibrium between CDKs and PP2A modulates phosphorylation of pRB, p107 and p130. Cell Cycle, 3(10), 1320-30, 2004.
- Garriga, J., Jayaraman, A.L., Limon, A., Jayadeva, G., Sotillo, E., Truongcao, M., Patsialou, A., Wadzinski, B.E., Grana, X. "Cell Cycle [ in press ]." , 2004.
- Wells, L, Kreppel, LK, Comer, FI, Wadzinski, BE, Hart, GW O-GlcNAc transferase is in a functional complex with protein phosphatase 1 catalytic subunits. J Biol Chem, 279(37), 38466-70, 2004.
- Wells, L., Kreppel, L.K., Comer, F.I., Wadzinski, B.E., Hart, G.W. "O-GlcNAc transferase is in a functional complex with protein phosphatase 1 catalytic subunits." J. Biol. Chem, 2004.
- Anderson, KA, Noeldner, PK, Reece, K, Wadzinski, BE, Means, AR Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex. J Biol Chem, 279(30), 31708-16, 2004.
- Anderson, K.A., Noeldner, P.K., Reece, K., Wadzinski, B.E., Means, A.R. "Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serinethreonine phosphatase 2A signaling complex." J.Biol. Chem. , 27931708-31716, 2004.
- Dagda, Ruben K, Zaucha, Julie A, Wadzinski, Brian E, Strack, Stefan A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis. J Biol Chem, 278(27), 24976-85, 2003.
- Colbran, Roger J, Carmody, Leigh C, Bauman, Patricia A, Wadzinski, Brian E, Bass, Martha A Analysis of specific interactions of native protein phosphatase 1 isoforms with targeting subunits. Methods Enzymol, 366156-75, 2003.
- Kloeker, Susanne, Reed, Robin, McConnell, Jamie L, Chang, Dennis, Tran, Kim, Westphal, Ryan S, Law, Brian K, Colbran, Roger J, Kamoun, Malek, Campbell, Kerry S, Wadzinski, Brian E Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with alpha4 protein. Protein Expr Purif, 31(1), 19-33, 2003.
- Kabashima, Tsutomu, Kawaguchi, Takumi, Wadzinski, Brian E, Uyeda, Kosaku Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc Natl Acad Sci U S A, 100(9), 5107-12, 2003.
- Strayhorn, W David, Wadzinski, Brian E A novel in vitro assay for deubiquitination of I kappa B alpha. Arch Biochem Biophys, 400(1), 76-84, 2002.
- Strayhorn, W.D., Wadzinski, B.E. "A novel in vitro assay for deubiquitination of IkB??." Arch. Biochem. Biophys, 40076-84, 2002.
- Wada, T, Miyata, T, Inagi, R, Nangaku, M, Wagatsuma, M, Suzuki, D, Wadzinski, B E, Okubo, K, Kurokawa, K Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells. J Am Soc Nephrol, 12(12), 2601-8, 2001.
- Wada, T., Miyata, T., Inagi, R., Nangaku, M., Wagatsuma, M., Suzuki, D., Wadzinski, B.E., Okubo, K., and Kurokawa, K "Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells." J. Am. Soc. Nephrol, 2001.
- Chiang, C W, Harris, G, Ellig, C, Masters, S C, Subramanian, R, Shenolikar, S, Wadzinski, B E, Yang, E Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood, 97(5), 1289-97, 2001.
- Chiang, C.-W., Harris, G., Ellig, C., Masters, S.C., Subramanian, R., Shenolikar, S., Wadzinski, B.E., and Yang, E "Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin-3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation." Blood, 971289-1297, 2001.
- Yang, J, Fan, G H, Wadzinski, B E, Sakurai, H, Richmond, A Protein phosphatase 2A interacts with and directly dephosphorylates RelA. J Biol Chem, 276(51), 47828-33, 2001.
- Bauman, A L, Apparsundaram, S, Ramamoorthy, S, Wadzinski, B E, Vaughan, R A, Blakely, R D Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A. J Neurosci, 20(20), 7571-8, 2000.
- Bauman, A.L., Apparsundaram, S., Ramamoorthy, S., Wadzinski, B.E., Vaughan, R.A., and Blakely, R.D "Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A." J. Neurosci, 207571-7578, 2000.
- Liu M, Parker LL, Wadzinski BE and Shieh BH "Reversible phosphorylation of the signal transduction complex in Drosophila photoreceptors." J Biol Chem, 275(16), 12194-12199, 2000.
- Liu, M, Parker, L L, Wadzinski, B E, Shieh, B H Reversible phosphorylation of the signal transduction complex in Drosophila photoreceptors. J Biol Chem, 275(16), 12194-9, 2000.
- MacMillan, L.B., Bass, M.A., Cheng, N., Howard, E.F., Tamura, M., Strack, S., Wadzinski, B.E., and Colbran, R.J "Brain Actin-Associated Protein Phosphatase 1 Holoenzyme Containing Spinophilin, Neurabin and Selected Catalytic Subunit Isoforms.." J. Biol. Chem., 27435845-35854, 1999.
- Price, N.E., Wadzinski, B.E., and Mumby, M.C "An Anchoring Factor Targets Protein Phosphatase 2A to Brain Microtubules." Mol. Brain Res., 7368-77., 1999.
- Price, N.E, Wadzinski, B.E., Mumby, M.C. "An anchoring factor targets protein phosphatase 2A to brain microtubules." Mol. Brain Res. , 7368-77, 1999.
- MacMillan, L B, Bass, M A, Cheng, N, Howard, E F, Tamura, M, Strack, S, Wadzinski, B E, Colbran, R J Brain actin-associated protein phosphatase 1 holoenzymes containing spinophilin, neurabin, and selected catalytic subunit isoforms. J Biol Chem, 274(50), 35845-54, 1999.
- Strack, S., Chang, D., Zaucha, J.A., Colbran, R.J., and Wadzinski, B.E "Cloning and Characterization of Ba Novel Regulatory Subunit of Protein Phosphatase 2A." FEBS Lett., 460462-466, 1999.
- Strack, S, Chang, D, Zaucha, J A, Colbran, R J, Wadzinski, B E Cloning and characterization of B delta, a novel regulatory subunit of protein phosphatase 2A. FEBS Lett, 460(3), 462-6, 1999.
- Strack S, Kini S, Ebner FF, Wadzinski BE and Colbran RJ "Differential cellular and subcellular localization of protein phosphatase 1 isoforms in brain." J Comp Neurol, 413(3), 373-384, 1999.
- Strack, S, Kini, S, Ebner, F F, Wadzinski, B E, Colbran, R J Differential cellular and subcellular localization of protein phosphatase 1 isoforms in brain. J Comp Neurol, 413(3), 373-84, 1999.
- Westphal, R.S., Coffee, R.L., Jr., Morratta, T., Pelech, S., and Wadzinski, B.E "Identification of Kinase/Phosphatase Signaling Modules Composed of p70S6 Kinase-Protein Phosphatase 2A (PP2A) and p21-Activated Kinase-PP2A." J. Biol.Chem., 274687-692, 1999.
- Filali, M., Li, S., Kim, H.W., Wadzinski, B.E., and Kamoun, M "Identification of a Type 6 Protein Ser/Thr Phosphatase Regulated by Interleukin-2 Stimulation." J. Cell. Biochem., 73153-163, 1999.
- Filali, M., li, S., Kim, H.W., Wadzinski, B.E., Kamoun, M. "Identification of a type 6 protein ser/thr phosphatase regulated by interleukin-2 stimulation." J Cell Biochem., 73153-163, 1999.
- Westphal, R S, Coffee, R L, Marotta, A, Pelech, S L, Wadzinski, B E Identification of kinase-phosphatase signaling modules composed of p70 S6 kinase-protein phosphatase 2A (PP2A) and p21-activated kinase-PP2A. J Biol Chem, 274(2), 687-92, 1999.
- Bryant JC, Westphal RS and Wadzinski BE "Methylated C- terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory B-alpha subunit." Biochem J, 339(2), 241-246, 1999.
- Bryant, J C, Westphal, R S, Wadzinski, B E Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit. Biochem J, 339 ( Pt 2)241-6, 1999.
- Kloeker, S. and Wadzinski, B.E "Purification and Identification of a Novel Subunit of Protein Serine/Threonine Phosphatase 4." J. Biol. Chem., 2745339-5347, 1999.
- Kloeker, S, Wadzinski, B E Purification and identification of a novel subunit of protein serine/threonine phosphatase 4. J Biol Chem, 274(9), 5339-47, 1999.
- Westphal, R S, Anderson, K A, Means, A R, Wadzinski, B E A signaling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A. Science, 280(5367), 1258-61, 1998.
- Westphal RS, Anderson KA, Means AR and Wadzinski BE "A signaling complex of Ca2+/calmodulin-dependent protein kinase IV and protein phosphatase 2A." Science, 2801258-1260, 1998.
- Strack S, Zaucha JA, Ebner FF, Colbran RJ and Wadzinski BE "Brain protein phosphatase 2A: developmental regulation and distinct cellular and subcellular localization by B subunits." J Comp Neurol, 392515-527, 1998.
- Strack, S, Zaucha, J A, Ebner, F F, Colbran, R J, Wadzinski, B E Brain protein phosphatase 2A: developmental regulation and distinct cellular and subcellular localization by B subunits. J Comp Neurol, 392(4), 515-27, 1998.
- Zaucha JA, Westphal RS and Wadzinski BE "Protein Phosphatase 2A Regulatory Subunits: cDNA Cloning and Analysis of mRNA Expression." Methods in Molecular Biology, 93279-291, 1998.
- Zaucha, J A, Westphal, R S, Wadzinski, B E protein phosphatase 2A regulatory subunits. cDNA cloning and analysis of mRNA expression. Methods Mol Biol, 93279-91, 1998.
- Colbran, R.J., Bass, M.A., McNeill, R.B., Bollen, M., Zhao, S., Wadzinski, B.E., and Strack, S "Association of Brain Protein Phosphatase 1 with Cytoskeletal Targeting/Regulatory Subunits.." J. Neurochem., 69920-929, 1997.
- Colbran, R J, Bass, M A, McNeill, R B, Bollen, M, Zhao, S, Wadzinski, B E, Strack, S Association of brain protein phosphatase 1 with cytoskeletal targeting/regulatory subunits. J Neurochem, 69(3), 920-9, 1997.
- Kloeker, S., Bryant, J.C., Strack, S., Colbran, R.J., and Wadzinski, B.E "Carboxymethylation of Nuclear Protein Serine/Threonine Phosphatase X." Biochem. J., 327481-486, 1997.
- Kloeker, S, Bryant, J C, Strack, S, Colbran, R J, Wadzinski, B E Carboxymethylation of nuclear protein serine/threonine phosphatase X. Biochem J, 327 ( Pt 2)481-6, 1997.
- Strack, S., Barban, M.A., Wadzinski, B.E., and Colbran, R.J "Differential Inactivation of Postsynaptic Density-Associated and Soluble Ca+2/Calmodulin-Dependent Protein Kinase II by Protein Phosphatases 1 and 2A." J. Neurochem., 682119-2128, 1997.
- Strack, S, Barban, M A, Wadzinski, B E, Colbran, R J Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J Neurochem, 68(5), 2119-28, 1997.
- Strack S, Westphal RS, Colbran RJ, Ebner FF and Wadzinski BE "Protein serine/threonine phosphatase 1 and 2A associate with and dephosphorylate neurofilaments." Mol Brain Res , 4915-28, 1997.
- Strack, S, Westphal, R S, Colbran, R J, Ebner, F F, Wadzinski, B E Protein serine/threonine phosphatase 1 and 2A associate with and dephosphorylate neurofilaments. Brain Res Mol Brain Res, 49(1-2), 15-28, 1997.
- Strack, S., Wadzinski, B.E., and Ebner, F.F "Localization of Calcium/Calmodulin-Dependent Protein Phosphatase, Calcineurin, in the Hindbrain and Spinal Cord of the Rat." J. Comp. Neurol., 37566-76, 1996.
- Strack, S, Wadzinski, B E, Ebner, F F Localization of the calcium/calmodulin-dependent protein phosphatase, calcineurin, in the hindbrain and spinal cord of the rat. J Comp Neurol, 375(1), 66-76, 1996.
- Peruski, L.F., Jr., Wadzinski, B.E., and Johnson, G.L "Analysis of the Multiplicity, Structure, and Function of Protein Serine/Threonine Phosphatases." Advances in Protein Phosphatases , 79-30, 1993.
- Wadzinski, B.E., Wheat, W.H., Jasper, S., Peruski, L.F., Jr., Lickteig, R.L., Johnson, G.L., and Klemm, D.J "Nuclear Protein Phosphatase 2A Dephosphorylates Protein Kinase A-Phosphorylated CREB and Regulates CREB Transcriptional Stimulation." Mol. Cell. Biol. , 132822-2834, 1993.
- Wadzinski, B E, Wheat, W H, Jaspers, S, Peruski, L F, Lickteig, R L, Johnson, G L, Klemm, D J Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Mol Cell Biol, 13(5), 2822-34, 1993.
- Wadzinski, B.E., Eisfelder, B.J., Peruski, L.F., Jr., Mumby, M.C., and Johnson, G.L "NH2-terminal Modification of the Phosphatase 2A Catalytic Subunit Allows Functional Expression in Mammalian Cells." J. Biol. Chem., 26716883-16888, 1992.
- Wadzinski, B E, Eisfelder, B J, Peruski, L F, Mumby, M C, Johnson, G L NH2-terminal modification of the phosphatase 2A catalytic subunit allows functional expression in mammalian cells. J Biol Chem, 267(24), 16883-8, 1992.
- Devaskar, S., Zahm, D.S., Holtzclaw, L., Chundu, K., and Wadzinski, B.E "Developmental Regulation of the Distribution of Rat Brain Insulin-Insensitive (Glut1) Glucose Transporter." Endocrinology, 1291530-1540, 1991.
- Devaskar, S, Zahm, D S, Holtzclaw, L, Chundu, K, Wadzinski, B E Developmental regulation of the distribution of rat brain insulin-insensitive (Glut 1) glucose transporter. Endocrinology, 129(3), 1530-40, 1991.
- Wadzinski, B.E., Shanahan, M.F., Seamon, K.B., and Ruoho, A.E "Localization of the Forskolin Photolabelling Site Within the Monosaccharide Transporter of Human Erythrocytes." Biochem. J., 272151-158, 1990.
- Wadzinski, B E, Shanahan, M F, Seamon, K B, Ruoho, A E Localization of the forskolin photolabelling site within the monosaccharide transporter of human erythrocytes. Biochem J, 272(1), 151-8, 1990.
- Wadzinski, B.E., Heasley, L.E., and Johnson, G.L "Multiplicity of Protein Serine-Threonine Phosphatases in PC12 Pheochromocytoma and FTO-2B Hepatoma Cells." J. Biol. Chem., 26521504-21508, 1990.
- Wadzinski, B E, Heasley, L E, Johnson, G L Multiplicity of protein serine-threonine phosphatases in PC12 pheochromocytoma and FTO-2B hepatoma cells. J Biol Chem, 265(35), 21504-8, 1990.
- Zorzano, A., Wilkinson, W., Kotliar, N., Thoidis, G., Wadzinski, B.E., Ruoho, A.E., and Pilch, P.F "Insulin-regulated Glucose Uptake in Rat Adipocytes is Mediated by Two Transporter Isoforms Present in at Least Two Vesicle Populations." J. Biol. Chem. , 26412358-12363, 19893.
- Wadzinski, B.E., Shanahan, M.F., Clark, R.B., and Ruoho, A.E "Identification of the Glucose Transporter in Mammalian Cell Membranes with a 125I-Forskolin Photoaffinity Label." Biochem. J., 255983-990, 1988.
- Wadzinski, B E, Shanahan, M F, Clark, R B, Ruoho, A E Identification of the glucose transporter in mammalian cell membranes with a 125I-forskolin photoaffinity label. Biochem J, 255(3), 983-90, 1988.
- Wadzinski, B E, Shanahan, M F, Ruoho, A E Derivatization of the human erythrocyte glucose transporter using a novel forskolin photoaffinity label. J Biol Chem, 262(36), 17683-9, 1987.
- Shanahan, M F, Wadzinski, B E, Lowndes, J M, Ruoho, A E Photoaffinity labeling of the human erythrocyte monosaccharide transporter with an aryl azide derivative of D-glucose. J Biol Chem, 260(20), 10897-900, 1985.
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