Dr. John E. Ladbury

Regular Member

The University of Texas MD Anderson Cancer Center
Department of Biochemistry and Molecular Biology

Research Interests:

• Biophysical analysis
• Tyrosine kinase signalling
• Protein complexes
• Protein-ligand interactions
• Drug development
• Structural-thermodynamic correlations

Specificity in Tyrosine Kinase-Mediated Signal Transduction - A Cellular to Atomic Level Investigation. Eukaryotic cells react to the external environment through interaction with membrane-bound receptors. Distinct types of receptors respond to different stimuli, but all are capable of sensing a binding event outside, and initiating signal transduction inside the cell. Most fundamental cellular processes including the cell cycle, migration, differentiation, survival, proliferation, immune response and metabolism are transduced through receptor tyrosine kinase (RTK)-mediated signal transduction. For transduction without corruption, the protein-protein interactions involved have to produce mutually exclusive responses. Aberrancies in these pathways are responsible for many disease states including cancer, immunodeficiency and diabetes. Many of the signalling pathways emanating from RTKs involve interactions of distinct domains (e.g., SH2, SH3, PTB). Our data suggest that binding of these domains to cognate ligands are not sufficiently specific to ensure mutual exclusivity of signalling. We are thus investigating alternative ways in which the integrity of a signal from a RTK can be maintained. Focusing on early signalling events (within 1 hour of stimulation) we are exploring the structural, biophysical, and cellular outcomes of protein complex formation at the receptor. Perturbations of these complexes by inhibiting assembly or modifying the time course (by making mutations) reveals how the exquisite sensitivity of early signalling complex formation can ensure specificity.

Selected Publications:

George R, Schuller AC, Harris R, Ladbury JE (2008) A phosphorylation-dependent gating mechanism controls the SH2 domain interactions of the Shc adaptor protein. J Mol Biol. 377:740-747.

Ahmed Z, Schuller AC, Suhling K, Tregidgo C, Ladbury JE (2008) Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling. Biochem J. 413:37-49.

Additional Publications

Program Affiliation:

Program in Genes and Development