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Jonathan Soboloff, PhD

Assistant Professor, Biochemistry

Assistant Professor, Fels Institute for Cancer Research and Molecular Biology

Telephone:  215-707-6567

Fax:  215-707-7536

Email: jonathan.soboloff@temple.edu

Department of Biochemistry

Fels Institute for Cancer Research and Molecular Biology

BSc, Science-Pre-Health Professions, University of Waterloo, Ontario, Canada, 1992

 

PhD, Physiology, University of Ottawa, Canada, 1993-1998 (Mentor:  Benjamin K. Tsang, PhD)

 

Postdoctoral Fellowship, University Health Network, Toronto, Canada (Mentor:  Stuart A. Berger, PhD, 1998-2002); University of Toronto, Canada (Mentor:  Michal Opas, PhD, 2003-2004); University of Maryland, Baltimore, MD (Mentor:  Donald L. Gill, PhD, 2004-2007)

 

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Ca2+ Signals and Cell Function

Ca2+ signals control multiple cell functions such as contraction and secretion in the short-term, transcriptional regulation in the medium term and long-term changes in cell growth and proliferation. Considering the vast range of different, and sometimes mutually exclusive physiological responses to increases in Ca2+ concentration, the nature of this response is very much dependent on both the cell type studied and the context of the Ca2+ signal. I have studied Ca2+ responses in a wide range of different types of cells, including mast cells, myeloid leukemia cells, vascular smooth muscle cells, granulosa cells, murine embryonic stem cells and cardiomyocytes. From this experience, I have come to understand that some aspects of Ca2+ signaling are universal, while others are unique to specific situations. Thus, the goal of my lab is to distinguish between cell-specific and universal characteristics of Ca2+ signals, and to associate these changes in Ca2+ concentration with specific changes in cell function.

Store-Operated Ca2+ Entry

Receptor-induced Ca2+ signals involve two closely coupled components – rapid, inositol 1,4,5-trisphosphate-mediated Ca2+ release from ER stores, followed by Ca2+ entry. A major mechanism of receptor-mediated Ca2+ entry is store-operated Ca2+ entry (SOCE), whereby endoplasmic reticulum (ER) Ca2+ depletion results in the activation of plasma membrane (PM) Ca2+ channels. This process has been extensively studied since its initial discovery 20 years ago. Finally, recent studies have identified the stromal-interacting molecule (STIM) and Orai families as the mediators of this process. Thus, changes in ER Ca2+ content are “sensed” by STIM1 which transduces its signal to the channel (Orai1) via ER-PM interactions (see Figure).

While the basic roles of STIM1 and Orai1 seem fairly clear, the roles for the other known members of the STIM and Orai families (STIM2, Orai2 and Orai3) are far less certain. Further, very little is known about the mechanisms of STIM-Orai interaction, the role(s) of STIM1 in the PM or potential cross-talk mechanisms between members of this pathway and other pathways. Last (but certainly not least), the potential involvement of these proteins in pathological situations has not been fully assessed.

Ca2+ Signals in Cancer Cells

Given the diverse role of Ca2+ in cellular physiology, there are numerous potential roles for store-operated Ca2+ entry in the process of transformation. In some of my prior studies, we established that several different types of cancer cells show enhanced sensitivity to inhibitors of Ca2+ entry, a phenomenon also observed in activated mast cells (leading to inflammatory disorders). While there have been numerous studies looking at the effects of STIM proteins on Ca2+ entry, there remains very little information on their relationship to cell fate. Moreover, before discovery of its role in Ca2+ signalling, STIM1 was studied as a potential tumour suppressor protein, while amplification of STIM2 has been associated with glioblastoma multiforme. While no link between the Ca2+-dependent properties of STIM proteins and transformation has been established, I am very interested in determining whether or not such a link exists.

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Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

19487696. Zhou Y, Mancarella S, Wang Y, Yue C, Ritchie M, Gill DL, Soboloff J, The short N-terminal domains of STIM1 and STIM2 control the activation kinetics of Orai1 channels. J Biol Chem 284:29(19164-8)2009 Jul 17

19473984. Deng X, Wang Y, Zhou Y, Soboloff J, Gill DL, STIM and Orai: dynamic intermembrane coupling to control cellular calcium signals. J Biol Chem 284:34(22501-5)2009 Aug 21

19376967. Wang Y, Deng X, Zhou Y, Hendron E, Mancarella S, Ritchie MF, Tang XD, Baba Y, Kurosaki T, Mori Y, Soboloff J, Gill DL, STIM protein coupling in the activation of Orai channels. Proc Natl Acad Sci U S A 106:18(7391-6)2009 May 5

19272522. Graham SJ, Black MJ, Soboloff J, Gill DL, Dziadek MA, Johnstone LS, Stim1, an endoplasmic reticulum Ca2+ sensor, negatively regulates 3T3-L1 pre-adipocyte differentiation. Differentiation 77:3(239-47)2009 Mar

18782202. Wang Y, Deng X, Hewavitharana T, Soboloff J, Gill DL, Stim, ORAI and TRPC channels in the control of calcium entry signals in smooth muscle. Clin Exp Pharmacol Physiol 35:9(1127-33)2008 Sep

18643752. Szabo E, Soboloff J, Dziak E, Opas M, Tamoxifen-inducible Cre-mediated calreticulin excision to study mouse embryonic stem cell differentiation. Stem Cells Dev :()2008 Jul 21

18635545. Hewavitharana T, Deng X, Wang Y, Ritchie MF, Girish GV, Soboloff J, Gill DL, Location and function of STIM1 in the activation of Ca2+ entry signals. J Biol Chem 283:38(26252-62)2008 Sep 19

17905723. Parvez S, Beck A, Peinelt C, Soboloff J, Lis A, Monteilh-Zoller M, Gill DL, Fleig A, Penner R, STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB J 22:3(752-61)2008 Mar

17602740. Hewavitharana T, Deng X, Soboloff J, Gill DL, Role of STIM and Orai proteins in the store-operated calcium signaling pathway. Cell Calcium 42:2(173-82)2007 Aug

17224452. Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, Gill DL, Ambudkar IS, Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. J Biol Chem 282:12(9105-16)2007 Mar 23

17217080. Soboloff J, Spassova M, Hewavitharana T, He LP, Luncsford P, Xu W, Venkatachalam K, van Rossum D, Patterson RL, Gill DL, TRPC channels: integrators of multiple cellular signals. Handb Exp Pharmacol :179(575-91)2007

17084918. Soboloff J, Spassova MA, Dziadek MA, Gill DL, Calcium signals mediated by STIM and Orai proteins--a new paradigm in inter-organelle communication. Biochim Biophys Acta 1763:11(1161-8)2006 Nov

17056714. Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL, A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci U S A 103:44(16586-91)2006 Oct 31

16978865. Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R, CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 16:20(2073-9)2006 Oct 24

16860747. Soboloff J, Spassova MA, Hewavitharana T, He LP, Xu W, Johnstone LS, Dziadek MA, Gill DL, STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ Entry. Curr Biol 16:14(1465-70)2006 Jul 25

16849592. Zhang Y, Soboloff J, Zhu Z, Berger SA, Inhibition of Ca2+ influx is required for mitochondrial reactive oxygen species-induced endoplasmic reticulum Ca2+ depletion and cell death in leukemia cells. Mol Pharmacol 70:4(1424-34)2006 Oct

16840689. Gill DL, Spassova MA, Soboloff J, Signal transduction. Calcium entry signals--trickles and torrents. Science 313:5784(183-4)2006 Jul 14

16766533. Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL, Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem 281:30(20661-5)2006 Jul 28

16537481. Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL, STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. Proc Natl Acad Sci U S A 103:11(4040-5)2006 Mar 14

16204251. Soboloff J, Spassova M, Xu W, He LP, Cuesta N, Gill DL, Role of endogenous TRPC6 channels in Ca2+ signal generation in A7r5 smooth muscle cells. J Biol Chem 280:48(39786-94)2005 Dec 2

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