Researchers with Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley have provided important new details into the activation of the epidermal growth factor receptor (EGFR), a cell surface protein that has been strongly linked to a large number of cancers and is a major target of cancer therapies.
"The more we understand about EGFR and the complex molecular machinery involved in the growth and proliferation of cells, the closer we will be to developing new and more effective ways to cure and treat the many different forms of cancer," says chemist Jay Groves, one of the leaders of this research. "Through a tour-de-force of quantitative biology techniques that included cutting edge time-resolved fluorescence spectroscopy in living cells, Nuclear Magnetic Resonance, and computational modeling, we've determined definitively how EGFR becomes activated through to its epidermal growth factor (EGF) ligand."
Groves, who holds joint appointments with Berkeley Lab's Physical Biosciences Division and UC Berkeley's Chemistry Department, and is also a Howard Hughes Medical Institute (HHMI) investigator is one of two corresponding authors of a paper in the journal Cell that describes this research. The paper is titled "Conformational Coupling across the Plasma Membrane in Activation of the EGF Receptor." The other corresponding author is John Kuriyan, who also holds joint appointments with Berkeley Lab, UC Berkeley and HHMI.
In high school biology classes we learn that genes contain coded instructions that are translated into the assembly of specific proteins. Many proteins, however, must be activated by post-translational processes such as autophosphorylation, the addition of phosphate. Protein activation can impact many important cellular processes including proliferation, differentiation and migration. Cancer is essentially a case of these cellular functions gone wild, often the result of problems with the EGFR. However, despite its well-established links to cancer, EGFR activation has only been partially understood.
"As a member of the large class of cell surface receptors known as receptor tyrosine kinases, EGFR features a ligand-binding domain on its extracellular side and a kinase domain on its intracellular side," Groves says. "The text-book explanation for EGFR activation is that the binding of EGFR's ligand, EGF, to its extracellular side induces dimerization of the receptor, which in turn brings together the kinase domains on the intracellular sides of the dimer, allowing them to phosphorylate one another."
Groves says while the picture is accurate, it is an oversimplification of the mechanics behind the process because isolated intracellular kinase domains in solution can be active on their own at relatively low concentration without EGF ligand-induced dimerization. Dimerization is the combining of two identical molecules into a single compound molecule.
Measuring autophosphorylation as a function of EGFR surface density in cells, Groves, Kuriyan and their colleagues found that structural coupling between the EGFR transmembrane helix and extracellular juxtamembrane modules in addition to EGF ligand-engagement is required for EGFR activation. This structural coupling permits dimerization to take place in the presence of the EGF ligand.