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.