David Siderovski

David Siderovski ((1966-07-05)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.

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

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.

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. He left the Amgen Research Institute in December 1998, after having contributed to three patents as a co-inventor.

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, chronicle his independent discovery of the RGS protein superfamily and determinations of their varied protein structures and cellular functions. One of these early reports was co-authored by two Nobel laureates: Alfred G. Gilman and Robert Lefkowitz.

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 (subsequently renamed RGS2); this cloning and sequencing work was conducted as a Queen's University undergraduate student in the Biochemistry laboratory of Dr. Donald R. Forsdyke. 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). What Siderovski originally identified as the G0S8-homology ("GH") domain 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.). 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. This foundational work by Siderovski on a new class of GPCR signaling regulators has been cited over 17,000 times according to Google Scholar and also resulted in Siderovski editing a two-volume set of Methods in Enzymology chapters devoted to these regulatory proteins.

Characterization of RGS protein RGS2

The first Regulator of G protein Signaling that Siderovski cloned, 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.). The Siderovski group, in a long-standing collaboration with the Structural Genomics Consortium node in Oxford, UK, 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. To begin to ascertain the physiological function(s) of RGS2, Siderovski worked with Amgen Inc. colleagues to ablate the Rgs2 locus in mice. These knockout mice were critical to observing that Rgs2 loss-of-function mutations lead to constitutive hypertension. Other vascular phenotypes in RGS2-null mice were seen to include persistent vasoconstriction, renovasculature abnormalities, and prolonged response to vasoconstrictors; 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.

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. 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 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. 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.

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, has promiscuous Galpha-directed GAP activity in vitro. Two patent applications were filed jointly by the Siderovski group and staff of The Coca-Cola Company.

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. In August 2014, Siderovski assumed the directorship of the West Virginia University School of Medicine MD/PhD Scholars Program.

In 2001, Siderovski was awarded a $210,000 New Investigator Award in the Pharmacological Sciences by the Burroughs Wellcome Fund. 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. 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.

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.

The family currently resides in Morgantown, West Virginia. During the 2014-15 and 2015-16 school years, Siderovski served the WVU Division 1 hockey team as a leader of the Student-Athlete Mentoring Program and as "DJ Dave" during home games.