Stephen Shears, Ph.D.

Senior Investigator

Signal Transduction Laboratory / Inositol Signaling Group

NIEHS

F239 Rall Building
111 T W Alexander Dr
Research Triangle Park, NC 27709

984-287-3483

shears@niehs.nih.gov

Research Topics

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.

Biography

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.

Selected Publications

  1. 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.

  2. Wang H, Nair VS, Holland AA, Capolicchio S, Jessen HJ, Johnson MK, Shears SB. Asp1 from Schizosaccharomyces pombe binds a [2Fe-2S](2+) cluster which inhibits inositol pyrophosphate 1-phosphatase activity. Biochemistry. 2015;54(42):6462-74.

  3. Shears SB. Intimate connections: Inositol pyrophosphates at the interface of metabolic regulation and cell signaling. J Cell Physiol. 2018;233(3):1897-1912.

  4. Gu C, Nguyen HN, Hofer A, Jessen HJ, Dai X, Wang H, Shears SB. The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis. J Biol Chem. 2017;292(11):4544-4555.

  5. Yousaf R, Gu C, Ahmed ZM, Khan SN, Friedman TB, Riazuddin S, Shears SB, Riazuddin S. Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse. PLoS Genet. 2018;14(3):e1007297.


This page was last updated on August 20th, 2018