Richard JH Wojcikiewicz, PhD
- Professor of Pharmacology
Research Programs and Affiliations
- Biomedical Sciences Program
- Cancer Research Institute
- Neuroscience Program
- Research Pillars
Education & Fellowships
- PhD: University of Sheffield, UK, 1985
- Intracellular signaling via InsP3 receptors and the ubiquitin/proteasome pathway.
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IP3 receptor regulation, the ubiquitin / proteasome pathway and intracellular signaling
IP3 is an intracellular messenger molecule formed at the plasma membrane when hormones, neurotransmitters or drugs stimulate cells. The effects of IP3 are mediated by proteins called IP3 receptors, channels that govern the release of calcium ions from the endoplasmic reticulum into the cell cytosol: this "calcium mobilization" is a central part of many cellular functions. My laboratory has been studying various aspects of IP3 receptor biochemistry and molecular biology for some time. Our primary focus at the moment is analyzing IP3 receptor down-regulation - a remarkable phenomenon by which IP3 receptors are rapidly depleted from cells when they are stimulated. This is a classic adaptive response that enables cells to adjust to their external environment and occurs during chronic exposure to drugs and perhaps in physiological and pathological situations. We are currently investigating the mechanism of IP3 receptor down-regulation and have discovered that it occurs because IP3 receptors are tagged with ubiquitin and then degraded by the proteosome. This is exciting because the ubiquitin / proteosome pathway is currently one of the "hot areas" of cell biology - is it becoming increasingly apparent that this pathway is the mechanism by which many important cellular proteins and misfolded proteins in the endoplasmic reticulum are degraded and is of major relevance to diseases (e.g. cancer, neurodegeneration, diabetes). Our immediate goals, then, are to define at the molecular level the pathway that leads to IP3 receptor degradation via the ubiquitin / proteasome pathway and to begin to build a picture of when, why and how cellular proteins are tagged with ubiquitin.
Alzayady, K., Panning, M.M., Kelley, G.G. and Wojcikiewicz, R.J.H. (2005) Involvement of the p97-Ufd1-Npl4 complex in the regulated endoplasmic reticulum-associated degradation of inositol 1,4,5-trisphosphate receptors. J. Biol. Chem. 280, 34530-34537.
Soulsby, M.D. and Wojcikiewicz, R.J.H. (2005) The type III inositol 1,4,5-trisphosphate receptor is phosphorylated by cAMP-dependent protein kinase at 3 sites. Biochem. J. 392, 493-497.
Alzayady, K. and Wojcikiewicz, R.J.H. (2005) The role of Ca2+ in triggering inositol 1,4,5-trisphosphate receptor ubiquitination. Biochem J. 392, 601-606.
Kelley, G.G., Kaproth-Joslin, K.A., Reks, S.E., Smrcka, A.V. and Wojcikiewicz, R.J.H. (2006) G-protein coupled receptor agonists activate endogenous phospholipase Cε and phospholipase Cβ3 in a temporally distinct manner. J. Biol. Chem. 281, 2639-2648.
Means, S., Smith, A.J., Shepard, J., Shadid, J., Fowler, J., Wojcikiewicz, R.J.H., Mazel, T., Smith G.D. and Wilson, B.S. (2006) Reaction Diffusion Modeling of Calcium Dynamics with Realistic ER Geometry. Biophys J. 91, 537-557.
Soulsby, M.D. and Wojcikiewicz, R.J.H. (2007) Calcium mobilization via type III inositol 1,4,5-trisphosphate receptors is not altered by PKA-mediated phosphorylation of serines 916, 934 and 1832. Cell Calcium 42, 261-270.
Pearce, M.M., Wang, Y., Kelley, G.G. and Wojcikiewicz, R.J.H. (2007) SPFH2 mediates the ERAD of IP3 receptors and other substrates in mammalian cells. J. Biol. Chem. 282, 20104-20115.
Hanson, C.J., Bootman, M.D., Distelhorst, C.W., Wojcikiewicz, R.J.H. and Roderick, H.L. (2008) Bcl-2 suppresses Ca2+ release through inositol 1,4,5-trisphosphate receptors and inhibits Ca2+ uptake by mitochondria without affecting ER calcium store content. Cell Calcium 44, 324-338.
Ito, J., Yoon, S-Y., Lee, B., Vanderhayden, V., Vermassen, E., Wojcikiewicz, R.J.H., Alfandari, D., De Smedt, H., Parys, J.B. and Fissore, R.A. (2008) Inositol 1,4,5-trisphosphate receptor 1, a widespread Ca2+ channel, is a novel substrate of polo-like kinase 1 in eggs. Dev. Biol. 320, 402-413.
Kuo, I.Y., Chan-Ling, T., Wojcikiewicz, R.J.H. and Hill, C.E. (2008) Limited intravascular coupling in the rodent brainstem and retina supports a role for glia in regional blood flow. J. Comp. Neurol. 511, 773-787.
Sliter, D., Kirkpatrick, D.S., Alzayady, K., Kubota, K., Gygi, S.P. and Wojcikiewicz, R.J.H. (2008) Mass spectral analysis of type I inositol 1,4,5-trisphosphate receptor ubiquitination. J. Biol. Chem. 283, 35319-35328.
Ellis, A., Goto, K., Brackenbury, T.D., Meaney, K.R., Falck, J.R., Wojcikiewicz, R.J.H. and Hill, C.E. (2009) Angiotensin II-dependency of the role of EETs and gap junctions in mediating EDHF activity in rat mesenteric arteries. J. Pharmacol. Exp. Ther. 330, 413-422.
Pearce, M.M.P., Wormer, D.B., Wilkens, S. and Wojcikiewicz, R.J.H. (2009) An ER membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of IP3 receptors. J. Biol. Chem. 284, 10433-10445.
Brodsky, J.L. and Wojcikiewicz R.J.H. (2009) Substrate specific mediators of ER associated degradation (ERAD). Curr. Opin. Cell Biol. 21, 516-21.
Wojcikiewicz, R.J.H., Pearce, M.M.P., Sliter, D. and Wang. Y. (2009) When worlds collide: IP3 receptors and the ERAD pathway. Cell Calcium 46, 147-153.
Wang, Y., Pearce, M.M.P., Sliter, D., Olzmann, J.A., Christianson, J.C., Kopito, R.R., Boeckmann, S., Gagen, C., Leichner, G., Roitelman, J. and Wojcikiewicz, R.J.H. (2009) SPFH1 and SPFH2 mediate the ubiquitination and degradation of inositol 1,4,5-trisphosphate receptors in muscarinic receptor-expressing HeLa cells. BBA 1793, 1710-1718
Sliter D.A., Aguiar, M., Gygi, S.P. and Wojcikiewicz, R.J.H. (2011) Activated inositol 1,4,5-trisphosphate receptors are modified by homogeneous LYS48- and LYS63-linked ubiquitin chains, but only LYS48-linked chains are required for degradation. J. Biol. Chem. 286, 1074-1082.
Lu, J.P., Wang, Y., Sliter, D.A., Pearce, M.M.P. and Wojcikiewicz, R.J.H. (2011) RNF170, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation. J. Biol. Chem. 286, 24426-24433.
Pednekar, D., Wang, Y., Fedotova, T.V. and Wojcikiewicz, R.J.H. (2011) Clustered hydrophobic amino acids in amphipathic helices mediate erlin 1 / 2 complex assembly. Biochem. Biophys. Res. Commun. 415, 135-140.
Wojcikiewicz, R.J.H. (2012) Inositol 1,4,5-trisphosphate receptor degradation pathways. Wiley Interdisciplinary Reviews (in press)