Haigler Laboratory
Department of Physiology & Biophysics
College of Medicine

Mechanisms of growth factor signal transduction;annexin calcium-binding proteins.

HARRY T. HAIGLER, Ph.D.

Vanderbilt University, 1977

Professor of Physiology & Biophysics

Our long-term goal is to understand the molecular and cellular mechanisms by which the hormone epidermal growth factor (EGF) controls growth and differentiation of eukaryotic cells. The EGF mitogenic pathway is activated by phosphorylation of certain regulatory proteins. Annexin I was found to be a high-affinity substrate for the EGF-stimulated kinase and to undergo reversible calcium-dependent binding to phospholipids on the cytosolic face of the plasma membrane. Recent research is directed toward determining the biological function of annexin I, how this function is modulated by phosphorylation, and the role it plays in transduction of the EGF-induced mitogenic signal.

Lab Projects

Annexin structure and function

Annexin XII Crystal Structure

We also are using the interaction of annexin XII (an annexin from hydra) with phospholipid bilayers as a model system to study the molecular mechanism of annexin:membrane interaction. A high resolution X-ray crystal structure of annexin XII revealed a homo-hexamer with intriguing properties (see illustration). On the basis of the hexamer structure, we proposed a novel mode of protein-phospholipid bilayer interaction that is distinct from the hydrophobic insertion of typical membrane proteins. Structure/function studies to test this model and its implications in formation of transmembrane ion channels and membrane aggregation and fusion are in progress.

EGF signalling

Tabby Mouse

In another project we are investigating the hypothesis that the EGF signalling pathway is involved in the human disease hypohidrotic ectodermal dysplasia (HED). HED is a congenital disease of skin morphogenesis affecting several ectodermal derivatives including sweat glands. Due to absence of sweat glands, HED patients have episodes of hyperthermia that can lead to mental retardation and death. The Tabby mouse is an ideal molecular model of human HED with both being caused by mutations in the same conserved gene. We have shown that expression of the EGF receptor is significantly reduced in patients with HED and in Tabby mice and propose that this reduction plays a causal role in the HED/Tabby phenotype. We are currently taking a candidate gene approach to the identification of the HED gene.

List of Recent Publications