""

about | Maps & Directions | contact | admissions | faculty | alumni & development | library | Tech Support Center | dean's office | Policies & Procedures

FAculty directory

Back to alphabetical index

 

Jonathan Soboloff, PhD

Jonathan Soboloff, PhD

 

Associate Professor, Biochemistry

Associate Professor, Fels Institute for Cancer Research and Molecular Biology

Telephone (Office):  215-707-6567

Telephone (Lab): 215-707-6568

Fax:  215-707-7536

Email: soboloff@temple.edu

 

Department of Biochemistry

Fels Institute for Cancer Research and Molecular Biology

 

Educational Background:

 

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)

 

Return to top

 

 

Research Interests:

 

Store-operated Ca2+ entry

Ca2+ signals mediate a vast range of both short-term (contraction, secretion) and long-term (mitogenesis, differentiation and survival) cellular events. Receptor-dependent changes in Ca2+ concentration 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 over 20 years ago, ultimately leading to the discovery of members of the Stromal-Interacting Molecule (STIM) and Orai families as the mediators of this process. Thus, changes in ER Ca2+ content are “sensed” by the ER Ca2+ sensors STIM1 and STIM2 which transduce this signal to the channel (Orai1) via ER-PM interactions (see Figure). These increases in cytosolic Ca2+ concentration are short-term, as excess Ca2+ is rapidly removed from the cytosol via pumps located on the plasma membrane (PMCA) and endoplasmic reticulum (SERCA).

 

image 1

 

Integration of SOCe in physiological responses

The short-term nature of Ca2+ signals has created a longstanding conceptual challenge; how do event that occur in seconds to minutes regulate physiological events that can last for hours to days? Recent investigations in my lab have revealed that the expression of STIM1 is controlled by members of the Early Growth Response (EGR) of zinc finger transcription factors along with the closely related Wilms Tumor suppressor 1 (WT1). EGR proteins are immediate early genes whose expression can be rapidly upregulated by the same receptors that initiate Ca2+ transients. Hence, our lab is greatly interested in understanding how changes in EGR protein expression patterns modulate receptor-mediated Ca2+ signals and assessing how this modulation relates to receptor-mediated control of physiological responses. To achieve our goals, we use a wide variety of molecular biological, biochemical and biophysical techniques to study transcriptional control of protein expression and Ca2+ signals. Model systems examined range from human cell lines to genetically manipulated mouse models.

 

Identification and characterization of new roles and targets for STIM1

Whereas STIM and Orai were originally envisioned as partners designed specifically for the control of store-operated Ca2+ entry, recent investigations by us and others have revealed a much wider role for STIM1. Hence, whereas the primary activator of STIM1 is loss of ER Ca2+, its ability to bind Ca2+ is dependent on both redox state and temperature. Further, in addition to Orai1, CaV1.2 and TRPC family members have both been identified as additional Ca2+ channels within the PM under the control of STIM1. In the process of investigating EGR-mediated changes in Ca2+ homeostasis during T cell activation, we have recently identified PMCA as a target for STIM1. Hence, during T cell activation, the cell dramatically reorganizes itself, such that STIM1 and PMCA come into close physically apposition. This leads to inhibition of PMCA function and local elevation of cytosolic Ca2+ concentration. While the critical role of Ca2+ in T cell activation has been well described, precisely how STIM1-mediated PMCA inhibition contributes to T cell activation is under current investigation in my lab.

 

Physiological and pathophysiological roles for STIM/Orai in control of bone density

The density of bone is under the control of osteoblasts (build bone) and osteoclasts (degrade bone). In collaboration with investigators at the University of Pittsburgh (Harry Blair) and the University of West Virginia (John Barnett), we have recently identified a critical role for Orai1 in osteoclast differentiation. Hence, in the absence of Orai1 expression and/or function, terminal osteoclast differentiation cannot complete. Hence, cells exhibit multiple markers and characteristics of mature osteoclasts, but fail to fuse into multi-nucleated cells. Ongoing collaborative efforts with the Blair and Barnett groups to determine the implications of these findings have revealed a novel and unexpected bone phenotype. We are also investigating the therapeutic potential of these findings towards the treatment of bone erosion associate with arthritis using novel inhibitors of Orai1 function.

 

Control of Ca2+ homeostasis and cell survival

Although SOCe serves an important signaling role, SOCe also cooperates with SERCA to maintain ER Ca2+ concentration by creating a source for Ca2+ pumping. We find that EGR/WT1 proteins also regulate SERCA expression. Further, since EGR/WT1 proteins function as tumor suppressors in cancer types of multiple lineages, dysregulation of both SERCA and STIM expression is a common feature of multiple tumor types. An important objective of this laboratory is to characterize these novel features of tumor cells, both to better understand tumor cell biology and to assess the potential of targeting Ca2+ entry pathways as a therapeutic strategy. Tumor types under investigation in the lab include Wilms Tumor, Acute Myeloid Leukemia, glioblastoma and rhabdomyosarcoma.

 

Return to top

 

 

LABORATORY PERSONNEl:

 

Postdoctoral Fellow:

Robert Hooper, PhD

215-707-6568

robert.hooper@temple.edu

Graduate Students:

Elsie Samakai

215-707-6568

elsie.samakai@temple.edu

 

Christina Go

215-707-6568

christina.go@temple.edu

Research Technician:

Long Le

215-707-6568

longle@temple.edu

URP Intern:

Maya Shmurak

215-707-6568

tud23572@temple.edu

 

Return to top

 

 

FUNDING HISTORY:

 

My lab is currently funded by grants from the National Institute of Health; we have also received funding from the American Heart Association and the Pennsylvania Department of Health.

 

Return to top

 

 

other selected publications:

 

Soboloff J, Désilets M, Tsang BK (1997) Ca2+ signaling in avian granulosa cells during ovarian follicular development. In: Etches R and Harvey S (eds.) Perspectives in Avian Endocrinology. London, UK: Journal of Endocrinology Ltd., pp 225-240.

 

Ritchie MF, Soboloff J* (2011) The STIM family of proteins. McGraw-Hill Yearbook of Science & Technology pg 323-324. * corresponding author


Soboloff, J (2013), "Mechanisms Regulating STIM Expression and Function in Ca2+ Signaling", in Simpson, A. (ed.), Calcium Signaling I: Regulation, Mechanisms, Effectors, Role in Disease and Recent Advances, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://hstalks.com/?t=BL0293385-Soboloff)

 

Return to top

 

 

PUBMED PUBLICATIONS :


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

25056876. Hooper R, Rothberg BS, Soboloff J, Neuronal STIMulation at rest. Sci Signal 7:335(pe18)2014 Jul 22

24492416. Wang X, Wang Y, Zhou Y, Hendron E, Mancarella S, Andrake MD, Rothberg BS, Soboloff J, Gill DL, Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat Commun 5:(3183)2014

23906672. Samakai E, Hooper R, Soboloff J, The critical role of STIM1-dependent Ca2+ signalling during T-cell development and activation. Int J Biochem Cell Biol 45:11(2491-5)2013 Nov

23568369. Hooper R, Samakai E, Kedra J, Soboloff J, Multifaceted roles of STIM proteins. Pflugers Arch 465:10(1383-96)2013 Oct

23348743. Gandhirajan RK, Meng S, Chandramoorthy HC, Mallilankaraman K, Mancarella S, Gao H, Razmpour R, Yang XF, Houser SR, Chen J, Koch WJ, Wang H, Soboloff J, Gill DL, Madesh M, Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest 123:2(887-902)2013 Feb 1

22914293. Soboloff J, Rothberg BS, Madesh M, Gill DL, STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13:9(549-65)2012 Sep

22546867. Robinson LJ, Mancarella S, Songsawad D, Tourkova IL, Barnett JB, Gill DL, Soboloff J, Blair HC, Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development. Lab Invest 92:7(1071-83)2012 Jul

22246182. Ritchie MF, Samakai E, Soboloff J, STIM1 is required for attenuation of PMCA-mediated Ca2+ clearance during T-cell activation. EMBO J 31:5(1123-33)2012 Mar 7

22144678. Yue C, Soboloff J, Gamero AM, Control of type I interferon-induced cell death by Orai1-mediated calcium entry in T cells. J Biol Chem 287:5(3207-16)2012 Jan 27

21769090. Soboloff J, Madesh M, Gill DL, Sensing cellular stress through STIM proteins. Nat Chem Biol 7:8(488-92)2011 Jul 18

21622185. Ritchie MF, Zhou Y, Soboloff J, WT1/EGR1-mediated control of STIM1 expression and function in cancer cells. Front Biosci (Landmark Ed) 16:(2402-15)2011 Jun 1

21385992. Eylenstein A, Gehring EM, Heise N, Shumilina E, Schmidt S, Szteyn K, Münzer P, Nurbaeva MK, Eichenmüller M, Tyan L, Regel I, Föller M, Kuhl D, Soboloff J, Penner R, Lang F, Stimulation of Ca2+-channel Orai1/STIM1 by serum- and glucocorticoid-inducible kinase 1 (SGK1). FASEB J 25:6(2012-21)2011 Jun

21074851. Ritchie MF, Zhou Y, Soboloff J, Transcriptional mechanisms regulating Ca(2+) homeostasis. Cell Calcium 49:5(314-21)2011 May

20929813. Wang Y, Deng X, Mancarella S, Hendron E, Eguchi S, Soboloff J, Tang XD, Gill DL, The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels. Science 330:6000(105-9)2010 Oct 1

20839232. Zhou Y, Lewis TL, Robinson LJ, Brundage KM, Schafer R, Martin KH, Blair HC, Soboloff J, Barnett JB, The role of calcium release activated calcium channels in osteoclast differentiation. J Cell Physiol 226:4(1082-9)2011 Apr

20679432. Hawkins BJ, Irrinki KM, Mallilankaraman K, Lien YC, Wang Y, Bhanumathy CD, Subbiah R, Ritchie MF, Soboloff J, Baba Y, Kurosaki T, Joseph SK, Gill DL, Madesh M, S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J Cell Biol 190:3(391-405)2010 Aug 9

20123987. Ritchie MF, Yue C, Zhou Y, Houghton PJ, Soboloff J, Wilms tumor suppressor 1 (WT1) and early growth response 1 (EGR1) are regulators of STIM1 expression. J Biol Chem 285:14(10591-6)2010 Apr 2

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 18:1(187-93)2009 Jan-Feb

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

15647288. He LP, Hewavitharana T, Soboloff J, Spassova MA, Gill DL, A functional link between store-operated and TRPC channels revealed by the 3,5-bis(trifluoromethyl)pyrazole derivative, BTP2. J Biol Chem 280:12(10997-1006)2005 Mar 25

15590052. Spassova MA, Soboloff J, He LP, Hewavitharana T, Xu W, Venkatachalam K, van Rossum DB, Patterson RL, Gill DL, Calcium entry mediated by SOCs and TRP channels: variations and enigma. Biochim Biophys Acta 1742:1-3(9-20)2004 Dec 6

15546997. Seth M, Sumbilla C, Mullen SP, Lewis D, Klein MG, Hussain A, Soboloff J, Gill DL, Inesi G, Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) gene silencing and remodeling of the Ca2+ signaling mechanism in cardiac myocytes. Proc Natl Acad Sci U S A 101:47(16683-8)2004 Nov 23

12785722. Trieselmann NZ, Soboloff J, Berger SA, Mast cells stimulated by membrane-bound, but not soluble, steel factor are dependent on phospholipase C activation. Cell Mol Life Sci 60:4(759-66)2003 Apr

12384154. Soboloff J, Zhang Y, Minden M, Berger SA, Sensitivity of myeloid leukemia cells to calcium influx blockade: application to bone marrow purging. Exp Hematol 30:10(1219-26)2002 Oct

11836247. Soboloff J, Berger SA, Sustained ER Ca2+ depletion suppresses protein synthesis and induces activation-enhanced cell death in mast cells. J Biol Chem 277:16(13812-20)2002 Apr 19

11466216. Soboloff J, Sasaki H, Tsang BK, Follicular stage-dependent tumor necrosis factor alpha-induced hen granulosa cell integrin production and survival in the presence of transforming growth factor alpha in vitro. Biol Reprod 65:2(477-87)2001 Aug

9915989. Soboloff J, Sorisky A, Désilets M, Tsang BK, Acyl chain length-specific ceramide-induced changes in intracellular Ca2+ concentration and progesterone production are not regulated by tumor necrosis factor alpha in hen granulosa cells. Biol Reprod 60:2(262-71)1999 Feb

8641205. Wan X, Désilets M, Soboloff J, Morris C, Tsang BK, Muscarinic activation inhibits T-type Ca2+ current in hen granulosa cells. Endocrinology 137:6(2514-21)1996 Jun

7578678. Soboloff J, Désilets M, Tsang BK, Influence of tumor necrosis factor alpha on intracellular Ca2+ in hen granulosa cells in vitro during follicular development. Biol Reprod 53:3(546-52)1995 Sep

7779993. Soboloff J, Wade MG, Wells G, Désilets M, Tsang BK, Influence of the muscarinic agonist carbachol on intracellular Ca2+ in chicken granulosa cells: I. Dependence on follicular maturation. Biol Reprod 52:4(721-8)1995 Apr

Return to top