Linda Pike

Alumni Endowed Professor of Biochemistry and Molecular Biophysics

    • 7513 Citations
    1977 …2018

    Research output per year

    If you made any changes in Pure these will be visible here soon.

    Personal profile

    Research interests

    The EGF receptor is a ubiquitously expressed cell surface receptor tyrosine kinase. Stimulation of cells with EGF leads to increases in metabolic activity and ultimately in cell proliferation. The EGF receptor and its homologous ErbB family members are over-expressed in many human tumors and several clinically useful drugs are directed against these proteins. My laboratory is interested in the the regulation of cell signaling via the EGF receptor and ErbB family members. We are particularly interested in the early steps that follow the binding of ligand and in understanding how the structure of the receptor enables transduction of the ligand binding signal through the membrane. In the membrane, the EGF receptor is thought to exist as a dimer, but upon binding ligand, the receptor dimerizes and its tyrosine kinase is activated. Using ligand binding analyses, we have shown that the EGF receptor exhibits negative cooperativity between binding sites in the active dimer and we are currently doing a mutational analysis to define the structural aspects of the EGF receptor that underlie this allosteric phenomenon. More recently, we have uncovered evidence for higher order oligomerization of the receptor, that appears to be susceptible to alteration by therapeutic inhibitors of the EGF receptor kinase. We are investigating how these higher order oligomers modulate EGF receptor-mediated signaling and how this effects the efficacy of molecularly targeted therapies. We previously developed a split luciferase enzyme complementation system that allows us to image EGF receptor dimerization in real time in live cells. We have now extended this system to allow us to measure the association of the EGF receptor with important downstream signaling molecules to allow us to understand how the binding of these proteins to the receptor affects the signaling capacity of the receptor. We have characterized the binding of eight different downstream signaling proteins to the EGF receptor stimulated by seven different EGF receptor ligands. Currently, we are using principal component analysis, clustering and network analysis to identify differences among the growth factors in the way they stimulate different pathways in the network. X-ray crystallographic structures exist for both the extracellular domain of the EGF receptor and the intracellular kinase domain. However, the structure of the C-terminal tail, to which all the signaling proteins bind, is unknown. The reason for this is that this ~200 amino acid segment is intrinsically disordered. Using FPOP footprinting and MD simulations, we are attempting to generate structural models that will tell us how the different proteins bind to the EGF receptor tail and how many might be able to bind to a single receptor. We are also doing a mutational analysis of the tail to determine whether it is just the intrinsic disorder that is important for the signaling function of the tale or whether there are auxiliary sequences that contribute to the regulation of protein-protein interactions.

    Fingerprint Dive into the research topics where Linda Pike is active. These topic labels come from the works of this person. Together they form a unique fingerprint.

    • 3 Similar Profiles

    Network Recent external collaboration on country level. Dive into details by clicking on the dots.

    Research Output

    Allosteric regulation of epidermal growth factor (EGF) receptor ligand binding by tyrosine kinase inhibitors

    Macdonald-Obermann, J. L. & Pike, L. J., Aug 31 2018, In : Journal of Biological Chemistry. 293, 35, p. 13401-13414 14 p.

    Research output: Contribution to journalArticle

    Open Access
  • 7 Scopus citations

    Epidermal growth factor receptors containing a single tyrosine in their C-terminal tail bind different effector molecules and are signaling-competent

    Gill, K., Macdonald-Obermann, J. L. & Pike, L. J., Dec 15 2017, In : Journal of Biological Chemistry. 292, 50, p. 20744-20755 12 p.

    Research output: Contribution to journalArticle

    Open Access
  • 4 Scopus citations

    Different Epidermal Growth Factor Receptor (EGFR) agonists produce unique signatures for the recruitment of downstream signaling proteins

    Ronan, T., Macdonald-Obermann, J. L., Huelsmann, L., Bessman, N. J., Naegle, K. M. & Pike, L. J., Mar 11 2016, In : Journal of Biological Chemistry. 291, 11, p. 5528-5540 13 p.

    Research output: Contribution to journalArticle

    Open Access
  • 24 Scopus citations

    EGFR oligomerization organizes kinase-active dimers into competent signalling platforms

    Needham, S. R., Roberts, S. K., Arkhipov, A., Mysore, V. P., Tynan, C. J., Zanetti-Domingues, L. C., Kim, E. T., Losasso, V., Korovesis, D., Hirsch, M., Rolfe, D. J., Clarke, D. T., Winn, M. D., Lajevardipour, A., Clayton, A. H. A., Pike, L. J., Perani, M., Parker, P. J., Shan, Y., Shaw, D. E. & 1 others, Martin-Fernandez, M. L., Oct 31 2016, In : Nature communications. 7, 13307.

    Research output: Contribution to journalArticle

    Open Access
  • 55 Scopus citations

    Different epidermal growth factor (EGF) receptor ligands show distinct kinetics and biased or partial agonism for homodimer and heterodimer formation

    Macdonald-Obermann, J. L. & Pike, L. J., Sep 19 2014, In : Journal of Biological Chemistry. 289, 38, p. 26178-26188 11 p.

    Research output: Contribution to journalArticle

    Open Access
  • 51 Scopus citations