John E. Ladbury, Ph.D.
Department of Biochemistry and Molecular Biology
Division of Basic Science Research
The University of Texas M.D. Anderson Cancer Center
B.S., Chemistry and Physics, University of London (1982)
M.S., Chemical Analysis, University of Greenwich, London (1987)
Ph.D., Polymer Chemistry, University of Greenwich, London (1990)
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. Perturbation 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. Furthermore, understanding the way in which these complexes modulate signaling networks provides insight into novel route to pharmaceutical intervention.
- Suen KM, Lin CC, George R, Melo FA, Biggs ER, Ahmed Z, Drake MN, Arur S, Arold ST and Ladbury JE. Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli. Nat Struct Mol Biol, 20(5):620-7 (2013). PubMed
- Ahmed Z, Lin CC, Suen KM, Melo FA, Levitt JA, Suhling K and Ladbury JE. Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity. J Cell Biol, 200(4):493-504 (2013). PubMed
- Chen Z, Vohidov F, Coughlin JM, Stagg LJ, Arold ST, Ladbury JE, and Ball ZT. Catalytic protein modification with dirhodium metallopeptides: specificity in designed and natural systems. J Am Chem Soc, 134(24):10138-10145 (2012). PubMed
- Lin CC, Melo FA, Ghosh R, Suen KM, Stagg LJ, Kirkpatrick J, Arold ST, Ahmed Z and Ladbury JE. Inhibition of Basal FGF Receptor Signaling by Dimeric Grb2. Cell, 149(7):1514-24 (2012). PubMed
- Di Domizio J, Zhang R, Stagg LJ, Gagea M, Zhuo M, Ladbury JE, and Cao W. Binding with nucleic acids or glycosaminoglycans converts soluble protein oligomers to amyloid. J Biol Chem, 287(1):736-47 (2012). PubMed
- Ramakrishnan M, Melo FA, Kinsey BM, Ladbury JE, Kosten TR and Orson FM. Probing cocaine-antibody interactions in buffer and human serum. PLoS One, e40518:1-12 (2012). PubMed
- Olsson TS, Ladbury JE, Pitt WR and Williams MA. Extent of enthalpy-entropy compensation in protein-ligand interactions. Protein Sci, 20(9):1607-18 (2011). PubMed
For more publications, see listing on PubMed.
The University of Texas at MD Anderson Cancer Center
6767 Bertner St., Room Number: BSRB, 7.8136A
Unit Number: 1000
Houston, TX 77030