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. Gu C, Liu J, Liu X, Zhang H, Luo J, Wang H, Locasale JW, Shears SB. Metabolic supervision by PPIP5K, an inositol pyrophosphate kinase/phosphatase, controls proliferation of the HCT116 tumor cell line. Proc Natl Acad Sci U S A. 2021;118(10).

  2. Wang Z, Jork N, Bittner T, Wang H, Jessen HJ, Shears SB. Rapid stimulation of cellular Pi uptake by the inositol pyrophosphate InsP8 induced by its photothermal release from lipid nanocarriers using a near infra-red light-emitting diode. Chem Sci. 2020;11(37):10265-10278.

  3. Zong G, Jork N, Hostachy S, Fiedler D, Jessen HJ, Shears SB, Wang H. New structural insights reveal an expanded reaction cycle for inositol pyrophosphate hydrolysis by human DIPP1. FASEB J. 2021;35(2):e21275.

  4. Li X, Gu C, Hostachy S, Sahu S, Wittwer C, Jessen HJ, Fiedler D, Wang H, Shears SB. Control of XPR1-dependent cellular phosphate efflux by InsP8 is an exemplar for functionally-exclusive inositol pyrophosphate signaling. Proc Natl Acad Sci U S A. 2020;117(7):3568-3574.

  5. Sahu S, Wang Z, Jiao X, Gu C, Jork N, Wittwer C, Li X, Hostachy S, Fiedler D, Wang H, Jessen HJ, Kiledjian M, Shears SB. InsP7 is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics. Proc Natl Acad Sci U S A. 2020;117(32):19245-19253.


This page was last updated on April 12th, 2013