Stephen B. Shears, Ph.D.
Signal Transduction Laboratory / Inositol Signaling Group
Building 101, Room F239
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Phosphates are a recurring theme in the signaling field. The bulky nature of the phosphate group establishes signaling specificity by imposing geometric constraints on ligand-protein and protein/protein interactions. The phosphate's negative charge at physiological pH also bestows specificity on its interactions with target proteins through multiple ionic and hydrogen bonds. The so-called "inositol pyrophosphates (IP7 and IP8) represent a highly-specialized example of the recruitment of multiple phosphates as a signaling paradigm. Our hypothesis is that IP7 and IP8 act at the intersection of cell signaling and metabolic homeostasis. Others have reported that inositol pyrophosphates regulate apoptosis, DNA repair, insulin secretion, and cell cycle progression. Nevertheless, the mechanisms of action of IP7 and IP8 remain controversial. We employ a multi-disciplinary approach to improve our knowledge of molecular actions of these polyphosphates, utilizing the tools of structural and cellular biology, biochemistry, and biophysics. We believe that the advances that we are making are relevant to developing new therapeutic approaches to life-threatening conditions such as inflammation, diabetes, obesity and cancer.
Dr. Shears obtained his Ph.D in Biochemistry in 1979 at the University of York in the U.K. Since 1988 he has been the Principal Investigator of the Inositol Signaling Group, currently within the Laboratory of Signal Transduction.
Wang H, Falck JR, Hall TM, Shears SB. Structural basis for an inositol pyrophosphate kinase surmounting phosphate crowding. Nat Chem Biol. 2011;8(1):111-6.
Wang H, DeRose EF, London RE, Shears SB. IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family. Nat Commun. 2014;5:4178.
Tsuzuki S, Matsumoto H, Furihata S, Ryuda M, Tanaka H, Sung EJ, Bird GS, Zhou Y, Shears SB, Hayakawa Y. Switching between humoral and cellular immune responses in Drosophila is guided by the cytokine GBP. Nat Commun. 2014;5:4628.
Yong ST, Nguyen HN, Choi JH, Bortner CD, Williams J, Pulloor NK, Krishnan MN, Shears SB. Identification of a functional nuclear translocation sequence in hPPIP5K2. BMC Cell Biol. 2015;16:17.
Pulloor NK, Nair S, McCaffrey K, Kostic AD, Bist P, Weaver JD, Riley AM, Tyagi R, Uchil PD, York JD, Snyder SH, García-Sastre A, Potter BV, Lin R, Shears SB, Xavier RJ, Krishnan MN. Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response. PLoS Pathog. 2014;10(2):e1003981.