Abstract
EREG and EPGN induce weak EGFR dimerization but sustained signaling compared with EGF.
Major finding: EREG and EPGN induce weak EGFR dimerization but sustained signaling compared with EGF.
Approach: Crystallization of EGFR dimers with ligands reveals a structural explanation for distinct signaling.
Impact: EGFR ligands modulate the receptor dimer structure, suggesting the potential for pharmacologic modulation.
The epidermal growth factor receptor (EGFR) is activated by seven different growth factors, which can induce distinct cellular responses. However, the mechanisms by which these different ligands can generate distinct signaling outcomes through the same receptor tyrosine kinase are unclear. There are four high-affinity EGFR ligands (EGF, TGFα, BTC, and HB-EGF), and three low-affinity ligands [epiregulin (EREG), epigen (EPGN), and amphiregulin (AREG)], which bind EGFR 10- to 100-fold more weakly. Freed and colleagues used crystallography and cellular studies to investigate EREG- and EPGN-driven EGFR signaling. A 2.9 Å crystal structure of EREG in complex with an EGFR extracellular dimer revealed a different structure from the previously reported TGFα/EGFR or EGF/EGFR dimers, suggesting that different EGFR ligands stabilize distinct EGFR conformations and lead to unique signaling. Specifically, EREG induced asymmetric EGFR dimers, contrasting with the symmetric dimers induced by TGFα or EGF. The asymmetric EREG-stabilized EGFR dimer was weaker than dimers stabilized by TGFα or EGF. Furthermore, a 3.0 Å crystal structure of EPGN-bound EGFR showed only a monomer, suggesting that EPGN also induces only weak EGFR dimerization. Despite inducing weaker dimerization, however, EREG and EPGN both induced robust EGFR signaling in breast cancer cells that was more sustained than the signaling induced by EGF. This sustained signaling resulted in enhanced cellular differentiation in response to EREG and EPGN, contrasting with the cell proliferation response induced by EGF. Altogether, these findings provide a structural explanation for the distinct signaling of different EGFR ligands, indicating that the stability and lifetime of the EGFR dimer specifies the signaling outcome. These results further suggest the potential for pharmacologic agents that modulate EGFR signaling, rather than blocking it entirely.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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