WEB资源
RESEARCH PROGRAMS AND AFFILIATIONS
研究兴趣
Intracellular signaling via InsP3 receptors and their regulation by the ubiquitin/proteasome pathway and Bcl-2 family proteins.
教育利益
咕咕叫ent Graduate 学生 are: Laura Szczesniak (MD/PhD), 高简森(博士), Fanghui Hua (PhD) and Caden Bonzerato (PhD)
教育
研究抽象
IP3 receptor regulation, the ubiquitin / proteasome pathway, the Bcl-2 protein family 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 (see diagram). 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 然后 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). 我们的近期目标, 然后, 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. As depicted in the diagram, in recent years we have discovered that IP3 receptor ubiquitination is mediated by a novel complex composed of the proteins erlin1 and erlin2, and the ubiquitin ligase RNF170, and that two ubiquitin chain types (K48-linked and K63-linked) are coupled to activated IP3 receptors. Using advanced techniques (e.g. cryo-EM) we are now defining at the structural level how IP3 receptors and the erlin1/2 complex interact. A second focus is characterizing the interaction of Bcl-2 family proteins (that control apoptosis) with IP3 receptors. We recently discovered that Bok (“Bcl-2-R得意洋洋的 O瓦里安 Killer”) binds constitutively to IP3 receptors and are defining the significance of this interaction. Because of the importance of IP3 receptors, the ubiquitin / proteasome pathway, and the Bcl-2 protein family to cell biology, this work is significant to both our understanding of normal physiology, 还有疾病, such as cancer and neurodegeneration.
最近的出版物
58. 皮尔斯,M.M.王，Y.凯利，G.G. 沃基凯维奇，R.J.H. (2007) SPFH2 mediates the ERAD of IP3 receptors and other substrates in mammalian cells. J. 医学杂志. 化学. 282, 20104-20115.
59. 汉森,C.J.布特曼，M.D.C.W.沃基凯维奇，R.J.H. 罗德里克，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. 细胞钙 44, 324-338.
60. 伊藤J.Yoon, S-Y.李，B.范德海登，V.Vermassen, E.沃基凯维奇，R.J.H.阿尔凡达里，D.德·斯梅特，H.帕里斯，J.B. 费索，R.A. (2008)肌醇,4,5-trisphosphate receptor 1, a widespread Ca2+ channel, is a novel substrate of polo-like kinase 1 in eggs. Dev. 医学杂志. 320, 402-413.
61. 郭,我.Y.陈玲，T.沃基凯维奇，R.J.H. 希尔，C。.E. (2008) Limited intravascular coupling in the rodent brainstem and retina supports a role for glia in regional blood flow. J. 电脑及相关知识. 神经. 511, 773-787.
62. 纵割机,D.D .柯克帕特里克.S.Alzayady, K.久保田，K.吉吉，S.P. 沃基凯维奇，R.J.H. (2008) Mass spectral analysis of type I inositol 1,4,5-trisphosphate receptor ubiquitination. J. 医学杂志. 化学. 283, 35319-35328.
63. 艾利斯,.， Goto, K.布拉肯伯里，T.D.米尼，K.R.福尔克，J.R.沃基凯维奇，R.J.H. 希尔，C。.E. (2009) Angiotensin II-dependency of the role of EETs and gap junctions in mediating EDHF activity in rat mesenteric arteries. J. 杂志. 经验值. 其他. 330, 413-422.
64. 皮尔斯,M.M.P.沃莫，D.B.威尔肯斯，S. 沃基凯维奇，R.J.H. (2009) An ER membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of IP3 receptors. J. 医学杂志. 化学. 284, 10433-10445.
65. 布罗斯基,J.L. 和沃基凯维奇R.J.H. (2009) Substrate specific mediators of ER associated degradation (ERAD). 咕咕叫. 当今. 细胞生物. 21, 516-21.
66. Wojcikiewicz R.J.H.皮尔斯，M.M.P.斯里尔，D. 和王. Y. (2009) When worlds collide: IP3 receptors and the ERAD pathway. 细胞钙 46, 147-153.
67. 王,Y.皮尔斯，M.M.P.斯里尔，D.奥尔兹曼，J.A.J .克里斯蒂安森.C.， Kopito, R.R.伯克曼，S.加根，C.莱希纳，G.罗特尔曼，J. 沃基凯维奇，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. 1793, 1710-1718
68. 纵割机维.A.阿吉亚尔，M.吉吉，S.P. 沃基凯维奇，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. 医学杂志. 化学. 286, 1074-1082.
69. 陆,J.P.王，Y.斯里尔，D.A.皮尔斯，M.M.P. 沃基凯维奇，R.J.H. (2011) RNF170, an endoplasmic reticulum membrane ubiquitin ligase, 介导肌醇1,4,5-trisphosphate receptor ubiquitination and degradation. J. 医学杂志. 化学. 286, 24426-24433.
70. Pednekar D.王，Y.费多托娃，T.V. 沃基凯维奇，R.J.H. (2011) Clustered hydrophobic amino acids in amphipathic helices mediate erlin 1 / 2 complex assembly. 物化学. Biophys. Res. Commun. 415, 135-140.
71. Wojcikiewicz R.J.H. (2012) Inositol 1,4,5-trisphosphate receptor degradation pathways. 电线会员. 透明. 信号. 1, 126-135.
72. 蔡,Y.C.莱希纳，G.S.皮尔斯，M.M.威尔逊，G.L.沃基凯维奇，R.J.罗特尔曼，J. 魏斯曼，A.M. (2012) Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. 摩尔. 医学杂志. 细胞. 23, 4484-4494.
73. Hirose, M.Kamoshita, M.藤原，K.加藤，T.Nakamura, A.沃基凯维奇，R.J.H.帕里斯，J.B.伊藤，J. 柏崎，n.n. (2013) Vitrification procedure decreases inositol 1,4,5-trisphosphate receptor expression, resulting in low fertility of pig oocytes. 动物科学. J. (新闻).
74. 舒尔曼J.J.赖特，F.A., Kaufmann, T 沃基凯维奇，R.J.H. (2013) The Bcl-2 protein family member Bok binds to the coupling domain of inositol 1,4,5-trisphosphate receptors and protects them from proteolytic cleavage. J. 医学杂志. 化学. 288, 25340-25349.
75. Sathanawongs,.藤原，K.加藤，T.广濑，M.Kamoshita, M.沃基凯维奇，R.J.H.帕里斯，J.B.伊藤，J. 柏崎，n.n. (2015) The effect of M-phase stage-dependent kinase inhibitors on inositol 1,4,5-triphosphate receptor 1 (IP3R1) expression and localization in pig oocytes. 动物科学. J. 86, 138-147.
76. 赖特,F.A.卢，J.P.斯里尔，D.A.纽约州杜普莱尔(duprire.鲁洛，G.A. 沃基凯维奇，R.J.H. (2015) A point mutation in the ubiquitin ligase RNF170 that causes autosomal dominant sensory ataxia destabilizes the protein and impairs inositol 1,4,5-trisphosphate receptor-mediated Ca2+ signaling. J. 医学杂志. 化学. 290, 13948-13957.
77. 舒尔曼J.J.赖特，F.A.汉，X.Zluhan, E.J.斯切斯尼亚克，L.M. 沃基凯维奇，R.J.H. (2016) The stability and expression level of Bok binds are governed by binding to inositol 1,4,5-trisphosphate receptors. J. 医学杂志. 化学. 291, 11820-11828.
78. 赖特,F.A. 沃基凯维奇，R.J.H. (2016) Inositol 1,4,5-trisphosphate receptor ubiquitination. 掠夺. 摩尔. 医学杂志. 反式. Sci. 141, 141-159.
79. 王,我.，史，C.赖特，F.A.郭，D.王，X.王博士.沃基凯维奇，R.J.H. 罗，J. (2017) Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in O瓦里安 Cancer Treatment. 癌症Res. 77, 3293 - 3305.
80. Wojcikiewicz R.J.H. (2018) The making and breaking of inositol 1, 4, 5 - trisphosphate receptor tetramers. 信使 6, 45-49.
81. 赖特,F.A.Bonzerato C.G.斯里尔，D.A. 沃基凯维奇，R.J.H. (2018) The erlin2 T65I mutation inhibits erlin1/2 complex-mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding. J. 医学杂志. 化学. 293, 15706-15714.
82. 舒尔曼J.J.斯切斯尼亚克，L.M.邦克，E.N.纳尔逊，H.A.罗伊，M.W.瓦格纳二世，L.A.，圣诞，D.I. 沃基凯维奇，R.J.H. (2019) Bok regulates mitochondrial fusion and morphology. 细胞死亡和Diff. doi: 10.1038/s41418-019-0327-4.83.
83. 高,X. 沃基凯维奇，R.J.H. (2020) The emerging link between IP3 receptor turnover and Hereditary Spastic Paraplegia. 细胞钙 86:102142. doi: 10.1016/j.盲肠.2019.102142.
84. 盾,Y.李，Y.崔凯.他，M.王，B.巴塔查尔吉，美国.朱，B.， Yago, T.张，K.邓，L.欧阳，K.文，A.考恩，D.B.宋，K.Yu, L.布罗菲，M.L.刘，X.韦利·西尔斯，J.，吴，H.黄，S.崔刚.川岛，Y.松本，H.Kodera, Y.沃基凯维奇，R.J.H.斯里瓦斯塔瓦，S.比肖夫，J.王博士.Z.Ley, K.陈，H. (2020) Epsin-mediated degradation of IP3R1 fuels atherosclerosis. Nat. Commun. 11(1):3984. doi: 10.1038/s41467-020-17848-4.
85. Szczesniak L.M.Bonzerato C.G.舒尔曼，J.J.，呸，A. 沃基凯维奇，R.J.H. (2021) Bok binds to a largely disordered loop in the coupling domain of type 1 inositol 1,4,5-trisphosphate receptor. 物化学. Biophys. Res Commun. 553, 180-186.
86. Szczesniak L.M.Bonzerato C.G. 沃基凯维奇，R.J.H. (2021) Identification of the Bok interactome using proximity labeling. 前面. 电池开发. 医学杂志. 9:689951. doi: 10.3389 / fcell.2021.689951.
87. 高,X.Bonzerato C.G. 沃基凯维奇，R.J.H. (2022) Binding of the erlin1/2 complex to the third intralumenal loop of IP3R1 triggers its ubiquitin-proteasomal degradation. J. 医学杂志. 化学. 298, 102026.
88. Bonzerato C.G.凯勒，K。.R.舒尔曼，J.J.高，X.斯切斯尼亚克，L.M. 沃基凯维奇，R.J.H. (2022) Endogenous Bok is stable at the endoplasmic reticulum and does not mediate proteasome inhibitor-induced apoptosis. 前面iers in 细胞 and Dev 医学杂志. 10, 1094302. doi: 10.3389 / fcell.2022.1094302.