ErbB2, a therapeutic target in cancer
Mark Lemmon group (University of Pennsylvania)
Using beamline 23ID-D and small-angle X-ray studies, Mark
Lemmon's group of the University of Pennsylvania has gained new insight on
the orphan receptor tyrosine kinase ErbB2, which is an important therapeutic
target in human cancer. ErbB2 is unique among the four human ErbB receptors,
including epidermal growth factor receptor (EGFR), in its ability to
transform cells in absence of ligand when it is over-expressed.
Ligand-induced activation of EGFR involves conformational changes in the
extracellular region, where an exposed "dimerization arm" of domain II
converts from a "tethered" state to an "extended" state. Previous structures
of ErbB2 were in an "extended" state, consistent with a constituitively
active "auto-activated" receptor that can form dimers independent of growth
factor. The new structure shows that this model is unlikely to pertain to
the ErbB2 sub-family. Drosophila melanogaster EGFR (dEGFR), although a close
relative of ErbB2, is strongly regulated by ligands. Like ErbB2, dEGFR also
is in an "extended" state. The new structure provides several mechanistic
possibilities, all different from the hEGFR model.
Figure: (A) tethered, extended, and
active states of human EGFR, with purple EGF, (B) human EGFR with bound EGF,
(C) ErbB2, (D) dEGFR.[ Figure reprinted by permission from Macmillan
Publishers Ltd: Nature,
Alvarado, D, Klein, DE, Lemmon, MA. ErbB2 resembles an autoinhibited
invertebrate epidermal growth factor receptor, Nature 461, 287-291 (2009).