Intracellular Signals

Research Summary

Stephen B. Shears, Ph.D., is head of the Inositol Signaling Group and holds a secondary appointment in the NIEHS Immunity, Inflammation, and Disease Laboratory. The group’s goal is to unravel the molecular mechanisms of cell-signaling processes mediated by inositol phosphates that mediate organismal and metabolic homeostasis. It is an emerging topic that is now attracting attention from the fields of immunology, inflammation, cancer, aging, as well as being relevant to research into metabolic disorders such as diabetes. Through these studies, the group aims to promote the development of new genetic and pharmacological approaches to improving human health and longevity in the face of environmental insults.

Phosphates are a recurring theme in the signaling field because of their ability to provide specificity to a molecule's interactions with other cellular entities. For example, the bulky nature of the phosphate group establishes signaling specificity by imposing geometric constraints on ligand-protein and protein/protein interactions. Additionally, the phosphate's negative charge at physiological pH is attracted to positively charged targets. Here, specificity comes from the participation of multiple ionic and hydrogen bonds.

Inositol polyphosphates — and particularly the pyrophosphorylated versions (IP7/IP8) — represent a highly-specialized example of the recruitment of multiple phosphates to engage in novel mechanisms of cellular regulation. As many as eight phosphates are positioned tightly around the six-carbon, inositol scaffold, thereby creating the most concentrated three dimensional arrays of phosphate groups found in nature. The Inositol Signaling Group has particular strengths in this area of research that has enabled it to make a number of important technical and conceptual advances.

The laboratory takes a multidisciplinary and collaborative approach, utilizing techniques from the fields of structural biology, biochemistry, pharmacology, molecular and cellular biology, flow cytometry, biophysics, and synthetic chemistry.

Shears received his Ph.D. in 1979 from the University of York in the U.K. He has published more than 180 articles in the leading scientific journals.