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Understanding Biased Agonism in Receptor Tyrosine Kinases

Event Details

Event Dates: 

Wednesday, February 28, 2018 - 3:30pm

Seminar Location: 

  • JSCBB Butcher Auditorium

Speaker Name(s): 

Mark Lemmon
Seminar Type/Subject

Scientific Seminar Type: 

  • Biochemistry Seminar

Event Details & Abstract: 

The 58 growth factor receptor tyrosine kinases (RTKs) provide a useful palette of signaling mechanisms used in biology by receptorswith a single transmembrane domain.  Although initial studies of examplessuch as the epidermal growth factor receptor (EGFR) suggested a simpleligand-induced dimerization mechanism, it is now clear that these receptors aremuch more complex than this, with substantial diversity across thesuperfamily.  Our studies of human EGFR activation by different activatingligands, combined with studies of invertebrate EGFRs, suggest a much morecomplicated picture for EGFR regulation.  Early work with the Drosophilaand C. elegans EGFRs suggested models for allosteric regulation ofdimeric EGF receptors.  More recently, we determined crystal structures ofthe human EGFR extracellular region bound to different activating ligands,revealing distinct structures with important implications for fine control ofEGFR activation.  Further investigation in cellular studies has revealedthat certain EGFR ligands function as partial or biased agonists of thereceptor, likely through a kinetic proofreading mechanism.