David Siderovski

David Siderovski, PhD

David Siderovski (left) and Gordon Gee
Born David Sideris
(1966-07-05) July 5, 1966
Toronto, Ontario
Residence Morgantown, West Virginia
Fields Pharmacologist, Medical education
Alma mater
Thesis Human Immunodeficiency Virus Type-1 Trans-activator of Transcription (HIV-1 Tat) (1997)
Doctoral advisor Tak Wah Mak
Known for Discovery of RGS proteins
Notable awards John J. Abel Award in 2004
Spouse Susan Siderovski
Children
  • D. Peter Siderovski
  • Karen Siderovski

David Siderovski (July 5, 1966) is an American pharmacologist who is known as a leader in the fields of GPCR signaling and medical education. Siderovski is the E.J. Van Liere Medicine Professor and Chair of Physiology and Pharmacology for the West Virginia University School of Medicine; since July 2015, Siderovski is also the interim Director of Research for the WVU Addictions Group, a component part of the WVU Centers for Neuroscience.[1]

Background

Siderovski was born in Toronto, Ontario to Thelma and Angelo Sideris. He was the youngest of two children.

Education

Siderovski attended Earl Haig Secondary School in North York, Ontario where he graduated in 1985.

In 1989, Siderovski graduated with a Bachelor of Science (Honours) degree from Queen's University in Kingston, Ontario. He majored in biochemistry and received the Prince of Wales Prize awarded to the one student graduating with an honours B.Sc. degree who is judged to have the best academic record at Queen's in that year's graduating class.[2]

Siderovski began his Ph.D training at the University of Toronto in May 1989. During his fifth year of Ph.D training, he also began full-time work as a Research Scientist in the Quantitative Biology Laboratory of the Amgen Research Institute (Toronto, Canada). He successfully defended his PhD thesis in November 1997.[3] He left the Amgen Research Institute in December 1998, after having contributed to three patents as a co-inventor.[4][5][6]

Early academic career

After completing his industrial postdoctoral position at the Amgen Research Institute in 1998, Siderovski joined the faculty at the University of North Carolina at Chapel Hill as a tenure-track Assistant Professor of Pharmacology. His earliest publications, starting with a brief original report in Current Biology,[7] chronicle his independent discovery of the RGS protein superfamily[8][9][10] and determinations of their varied protein structures[11][12] and cellular functions.[13] One of these early reports[11] was co-authored by two Nobel laureates: Alfred G. Gilman and Robert Lefkowitz.

Contributions to science

Discovery and characterizations of RGS proteins

Siderovski was the first to report the cloning and sequencing of a cDNA encoding an RGS protein family member: 'G0/G1-switch gene-8' or G0S8[14][15] (subsequently renamed RGS2[16]); this cloning and sequencing work was conducted as a Queen's University undergraduate student in the Biochemistry laboratory of Dr. Donald R. Forsdyke.[17] Before the discovery of RGS proteins, the duration of heterotrimeric G-protein signaling was thought to be modulated by only two factors: the intrinsic GTP hydrolysis rate of the Gα subunit and acceleration of that rate by some specialized Gα effectors (i.e., phospholipase C-beta isoforms[18]). What Siderovski originally identified as the G0S8-homology ("GH") domain[7] in proteins from several eukaryotic genomes (human, Drosophila melanogaster, Caenorhabditis elegans, the budding yeast Saccharomyces cerevisiae) is now known as the "RGS domain", an approximately 130 amino-acid domain that contacts the Gα switch regions to stabilize the transition state, thus accelerating GTP hydrolysis (i.e., RGS proteins act as GTPase-accelerating proteins or “GAPs” for Gα-GTP; e.g., ref.[11]). Discovery of a superfamily of RGS domain-containing proteins that negatively regulate Gα-dependent signaling resolved a prior paradox that GPCR-stimulated signals are seen to terminate much faster in vivo than predicted from the slow GTP hydrolysis rates exhibited by purified Gα subunits in vitro. RGS proteins are now considered key desensitizers of heterotrimeric G protein signaling and, as such, as new drug discovery targets.[19][20] This foundational work by Siderovski on a new class of GPCR signaling regulators has been cited over 17,000 times according to Google Scholar[21] and also resulted in Siderovski editing a two-volume set of Methods in Enzymology chapters devoted to these regulatory proteins.[22][23]

Characterization of RGS protein RGS2

The first Regulator of G protein Signaling that Siderovski cloned,[15] RGS2, was subsequently found to be a potent GTPase-accelerating protein (GAP) for G-alpha-q in vitro and an attenuator of Gq-coupled receptor signaling in cell-based assays (e.g., ref.[13]). The Siderovski group, in a long-standing collaboration with the Structural Genomics Consortium node in Oxford, UK,[24] used x-ray crystallography and site-directed mutagenesis to ascertain the role of three critical residues within RGS2 that control its unique selectivity for G-alpha-q family subunits.[25] To begin to ascertain the physiological function(s) of RGS2, Siderovski worked with Amgen Inc. colleagues to ablate the Rgs2 locus in mice.[26] These knockout mice were critical to observing that Rgs2 loss-of-function mutations lead to constitutive hypertension.[27] Other vascular phenotypes in RGS2-null mice were seen to include persistent vasoconstriction, renovasculature abnormalities, and prolonged response to vasoconstrictors;[27][28] all of these mouse phenotypes are consistent with an increase in G-alpha-q signaling given the loss of RGS2 GAP activity. These mouse-based studies have helped inform subsequent studies of the human condition, in which genetic variations have now been identified in the human RGS2 gene between hypertensives and normotensives.[29]

Discovery of the GoLoco motif

Using then-nascent techniques of bioinformatics and genome data-mining to uncover novel regulators of G-protein signaling, Siderovski discovered a unique, second Gα interaction site, the GoLoco motif, within RGS12 and RGS14 that is shared with a number of non-RGS-domain-containing proteins.[30] The GoLoco/Gα interaction leads to inhibition of spontaneous nucleotide release – an activity previously thought to be the exclusive role of the Gβγ subunit. Siderovski's 2002 Nature paper[31] established the structural determinants of GoLoco motif biochemical activity and binding selectivity by describing the first high-resolution structure of a GoLoco motif/Gα complex. The true value of this GoLoco motif discovery was fully realized in subsequent 2003 Science and 2004 Cell papers describing that GoLoco motif-containing proteins GPR-1 and GPR-2 are critical for asymmetric cell division in the Caenorhabditis elegans zygote.[32][33] Those findings cemented the emerging view that GoLoco motif proteins act in a hitherto unexpected arena: namely, establishing a novel, receptor-independent Gα nucleotide cycle that controls microtubule dynamics, mitotic spindle pulling forces, and the act of chromosomal segregation during cell division.[34]

Characterization of RGS protein RGS21

With sponsored research funding (2007-2013) from The Coca-Cola Company on the molecular determinants of taste, Siderovski's group was the first to establish that RGS21, a small RGS protein whose mRNA transcript is uniquely expressed in taste bud cells,[35] has promiscuous Galpha-directed GAP activity in vitro.[36] Two patent applications were filed jointly by the Siderovski group and staff of The Coca-Cola Company.[37][38]

Contributions to medical education

From 2006 to 2012, Siderovski was the Thomas J. Dark Basic Science Director of UNC's Medical Scientist Training Program and directly responsible for assisting MD/PhD combined-degree trainees in identifying their PhD mentors and for overseeing their progress to PhD completion.[39] In August 2014, Siderovski assumed the directorship of the West Virginia University School of Medicine MD/PhD Scholars Program.[40]

Honors

In 2001, Siderovski was awarded a $210,000 New Investigator Award in the Pharmacological Sciences by the Burroughs Wellcome Fund.[41] In 2004, Siderovski was named the top American Pharmacologist under 40 and awarded the John J. Abel Award by the American Society for Pharmacology and Experimental Therapeutics.[42] In 2006, the University of North Carolina at Chapel Hill awarded Siderovski the Phillip and Ruth Hettleman Prize for Artistic and Scholarly Achievement for his research on regulators of G protein signaling.[43]

Personal life

Siderovski met his wife while in college and they married in 1989. Their son D. Peter Siderovski was born in 1993. Their daughter Karen Siderovski was born in 1997. Siderovski's wife published a book on Tularemia in 2006, in which Siderovski contributed some graphical elements.[44]

The family currently resides in Morgantown, West Virginia. During the school year, Siderovski serves the WVU Division 1 hockey team as a leader of the Student-Athlete Mentoring Program[45] and as "DJ Dave" during home games.

References

  1. ↑ "WVU Centers for Neuroscience". WVU Centers for Neuroscience. Retrieved 30 August 2015.
  2. ↑ "Prince of Wales Prizes". Automatic Awards Open to All Upper Year Students. Queen's University. Retrieved 11 August 2015.
  3. ↑ Siderovski, David Peter (1997). Human immunodeficiency virus type-1 trans-activator of transcription (HIV-1 Tat): Random mutagenesis and interaction with PKR (PDF). University of Toronto. Retrieved 2015-08-04.
  4. ↑ "Methods of modulating T-cell activation WO 1997041438 A1". Retrieved 9 August 2015.
  5. ↑ "Apoptosis-inducing factor CA 2352467 A1". Retrieved 9 August 2015.
  6. ↑ "Apoptosis-inducing factor CA 2352467 C". Retrieved 9 August 2015.
  7. 1 2 Siderovski DP, Hessel A, Chung S, Mak TW, Tyers M (February 1996). "A new family of regulators of G-protein-coupled receptors?". Curr Biol 6 (2): 211–2. doi:10.1016/S0960-9822(02)00454-2. PMID 8673468.
  8. ↑ Snow BE, Antonio L, Suggs S, Gutstein HB, Siderovski DP (April 1997). "Molecular cloning and expression analysis of rat Rgs12 and Rgs14". Biochem Biophys Res Commun 233 (3): 770–7. doi:10.1006/bbrc.1997.6537. PMID 9168931.
  9. ↑ Snow BE, Antonio L, Suggs S, Siderovski DP (January 1998). "Cloning of a retinally abundant regulator of G-protein signaling (RGS-r/RGS16): genomic structure and chromosomal localization of the human gene". Gene 206 (2): 247–53. doi:10.1016/s0378-1119(97)00593-3. PMID 9469939.
  10. ↑ Siderovski DP, Strockbine B, Behe CI (1999). "Whither goest the RGS proteins?". Crit Rev Biochem Mol Biol 34 (4): 215–51. doi:10.1080/10409239991209273. PMID 10517644.
  11. 1 2 3 Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, Chung S, Mangion J, Gilman AG, Lefkowitz RJ, Siderovski DP (July 1998). "GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain". J Biol Chem 273 (28): 17749–55. doi:10.1074/jbc.273.28.17749. PMID 9651375.
  12. ↑ Snow BE, Krumins AM, Brothers GM, Lee SF, Wall MA, Chung S, Mangion J, Arya S, Gilman AG, Siderovski DP (October 1998). "A G protein gamma subunit-like domain shared between RGS11 and other RGS proteins specifies binding to Gbeta5 subunits". Proc Natl Acad Sci U S A 95 (22): 13307–12. doi:10.1073/pnas.95.22.13307. PMC 23793. PMID 9789084.
  13. 1 2 Ingi T, Krumins AM, Chidiac P, Brothers GM, Chung S, Snow BE, Barnes CA, Lanahan AA, Siderovski DP; et al. (September 1998). "Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity". J Neurosci 18 (18): 7178–88. PMID 9736641.
  14. ↑ Siderovski, DP; Blum, S; Forsdyke, RE; Forsdyke, DR (October 1990). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA Cell Biol. 9 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID 1702972.
  15. 1 2 Siderovski, DP; Heximer, SP; Forsdyke, DR (February 1994). "A human gene encoding a putative basic helix-loop-helix phosphoprotein whose mRNA increases rapidly in cyclohgeximide-treated blood mononuclear cells". DNA Cell Biol. 13 (2): 125–47. doi:10.1089/dna.1994.13.125. PMID 8179820.
  16. ↑ Koelle, MR; Horvitz, HR (January 1996). "EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins". Cell 84 (1): 115–25. doi:10.1016/s0092-8674(00)80998-8. PMID 8548815.
  17. ↑ "Donald R. Forsdyke, M.B., B. S., B. A., Ph.D". Forsdyke, Donald R. Queen's University. Retrieved 11 August 2015.
  18. ↑ Berstein, G; Blank, JL; Jhon, DY; Exton, JH; Rhee, SG; Ross, EM (August 1992). "Phospholipase C-beta 1 is a GTPase-activating protein for Gq/11, its physiologic regulator". Cell 70 (3): 411–8. doi:10.1016/0092-8674(92)90165-9. PMID 1322796.
  19. ↑ Neubig, RR; Siderovski, DP (March 2002). "Regulators of G-protein signaling as new central nervous system drug targets". Nat Rev Drug Discov. 1 (3): 187–97. doi:10.1038/nrd747. PMID 12120503.
  20. ↑ Kimple, AJ; Bosch, DE; Giguere, PM; Siderovski, DP (September 2011). "Regulators of G-protein signaling and their Galpha substrates: promises and challenges in their use as drug discovery targets". Pharmacol Rev. 63 (3): 728–49. doi:10.1124/pr.110.003038. PMID 21737532.
  21. ↑ Siderovski. "Citation Counts". Google Scholar Citations. Google Scholar. Retrieved 12 August 2015.
  22. ↑ Siderovski, David P. (2004). Regulators of G-protein signalling, Part A (Volume 389 ed.). San Diego, CA.: Elsevier Academic Press. ISBN 978-0-12-182794-6. Retrieved 13 August 2015.
  23. ↑ Siderovski, David P. (2004). Regulators of G-protein signalling, Part B (Volume 390 ed.). San Diego, CA.: Elsevier Academic Press. ISBN 978-0-12-182795-3. Retrieved 13 August 2015.
  24. ↑ Soundararajan, M; Willard, FS; Kimple, AJ; Turnbull, AP; Ball, LJ; Schoch, GA; Gileadi, C; Fedorov, OY; Dowler, EF; Higman, VA; Hutsell, SQ; Sundström, M; Doyle, DA; Siderovski, DP (April 2008). "Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits". Proc Natl Acad Sci U S A. 105 (17): 6457–62. doi:10.1073/pnas.0801508105. PMC 2359823. PMID 18434541.
  25. ↑ Kimple, AJ; Soundararajan, M; Hutsell, SQ; Roos, AK; Urban, DJ; Setola, V; Temple, BR; Roth, BL; Knapp, S; Willard, FS; Siderovski, DP (July 2009). "Structural determinants of G-protein alpha subunit selectivity by regulator of G-protein signaling 2 (RGS2)". J Biol Chem. 284 (29): 19402–11. doi:10.1074/jbc.m109.024711. PMC 2740565. PMID 19478087.
  26. ↑ Oliveira-Dos-Santos, AJ; Matsumoto, G; Snow, BE; Bai, D; Houston, FP; Whishaw, IQ; Mariathasan, S; Sasaki, T; Wakeham, A; Ohashi, PS; Roder, JC; Barnes, CA; Siderovski, DP; Penninger, JM (October 2000). "Regulation of T cell activation, anxiety, and male aggression by RGS2". Proc Natl Acad Sci U S A 97 (22): 12272–7. doi:10.1073/pnas.220414397. PMC 17331. PMID 11027316. Retrieved 11 August 2015.
  27. 1 2 Heximer, SP; Knutsen, RH; Sun, X; Kaltenbronn, KM; Rhee, MH; Peng, N; Oliveira-Dos-Santos, A; Penninger, JM; Muslin, AJ; Steinberg, TH; Wyss, JM; Mecham, RP; Blumer, KJ (February 2003). "Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice". J Clin Invest. 111 (4): 445–52. doi:10.1172/jci200315598. PMC 151918. PMID 12588882. Retrieved 11 August 2015.
  28. ↑ Tang, KM; Wang, GR; Lu, P; Karas, RH; Aronovitz, M; Heximer, SP; Kaltenbronn, KM; Blumer, KJ; Siderovski, DP; Zhu, Y; Mendelsohn, ME (December 2003). "Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure". Nat Med. 9 (12): 1506–12. doi:10.1038/nm958. PMID 14608379.
  29. ↑ Tsang, S; Woo, AY; Zhu, W; Xiao, RP (January 2010). "Deregulation of RGS2 in cardiovascular diseases". Front Biosci (Schol Ed). 2: 547–57. PMC 2815333. PMID 20036967. Retrieved 12 August 2015.
  30. ↑ Siderovski, DP; Diversé-Pierluissi, Ma; De Vries, L (September 1999). "The GoLoco motif: a Galphai/o binding motif and potential guanine-nucleotide exchange factor.". Trends in Biochemical Sciences 24 (9): 340–1. doi:10.1016/s0968-0004(99)01441-3. PMID 10470031.
  31. ↑ Kimple, RJ; Kimple, ME; Betts, L; Sondek, J; Siderovski, DP (25 April 2002). "Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits.". Nature 416 (6883): 878–81. doi:10.1038/416878a. PMID 11976690.
  32. ↑ Colombo, K; Grill, SW; Kimple, RJ; Willard, FS; Siderovski, DP; Gönczy, P (20 June 2003). "Translation of polarity cues into asymmetric spindle positioning in Caenorhabditis elegans embryos.". Science 300 (5627): 1957–61. doi:10.1126/science.1084146. PMID 12750478.
  33. ↑ Afshar, K; Willard, FS; Colombo, K; Johnston, CA; McCudden, CR; Siderovski, DP; Gönczy, P (15 October 2004). "RIC-8 is required for GPR-1/2-dependent Galpha function during asymmetric division of C. elegans embryos.". Cell 119 (2): 219–30. doi:10.1016/j.cell.2004.09.026. PMID 15479639.
  34. ↑ Willard, FS; Kimple, RJ; Siderovski, DP (2004). "Return of the GDI: the GoLoco motif in cell division.". Annual Review of Biochemistry 73: 925–51. doi:10.1146/annurev.biochem.73.011303.073756. PMID 15189163.
  35. ↑ von Buchholtz, L; Elischer, A; Tareilus, E; Gouka, R; Kaiser, C; Breer, H; Conzelmann, S (March 2004). "RGS21 is a novel regulator of G protein signalling selectively expressed in subpopulations of taste bud cells". Eur J Neurosci. 19 (6): 1535–44. doi:10.1111/j.1460-9568.2004.03257.x. PMID 15066150.
  36. ↑ Cohen, SP; Buckley, BK; Kosloff, M; Garland, AL; Bosch, DE; Cheng, G Jr; Radhakrishna, H; Brown, MD; Willard, FS; Arshavsky, VY; Tarran, R; Siderovski, DP; Kimple, AJ (December 2012). "Regulator of G-protein signaling-21 (RGS21) is an inhibitor of bitter gustatory signaling found in lingual and airway epithelia". J Biol Chem. 287 (50): 41706–19. doi:10.1074/jbc.m112.423806. PMC 3516720. PMID 23095746. Retrieved 12 August 2015.
  37. ↑ "CELL LINES COMPRISING ENDOGENOUS TASTE RECEPTORS AND THEIR USES". United States Patent Application 20130040316. US Patent & Trademark Office. Retrieved 12 August 2015.
  38. ↑ "CELL LINES COMPRISING ENDOGENOUS TASTE RECEPTORS AND THEIR USES". United States Patent Application 20130040317. US Patent & Trademark Office. Retrieved 12 August 2015.
  39. ↑ "Leadership". UNC MD-PhD Program (circa March 24, 2012). Internet Archive Wayback Machine. Archived from the original on March 24, 2012. Retrieved 12 August 2015.
  40. ↑ "Siderovski Chosen to Oversee M.D./PH.D. Scholars Program". School of Medicine > Home > News > Story. WVU School of Medicine. Retrieved 13 August 2015.
  41. ↑ Burroughs Wellcome Fund (2001). "Burroughs Wellcome Fund 2001 Annual Report" (PDF). Burroughs Wellcome Fund. Retrieved 2015-08-07.
  42. ↑ ASPET (2004-01-01). "ASPET Award Winners for 2004" (PDF). ASPET. Retrieved 2015-08-04.
  43. ↑ UNC Gazette (2006-09-27). "Four faculty awarded Hettleman Prizes for artistic, scholarly achievement". UNC University Gazette. Retrieved 2015-08-07.
  44. ↑ Siderovski, Susan Hutton (2006). Tularemia. Chelsea House Publishers. Retrieved 2015-08-06.
  45. ↑ "Player Academic Initiative Announced". WVU Ice Hockey. September 9, 2014. Retrieved 30 August 2015.

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