PodcastStructural Biology

Science Signaling Podcast: 2 December 2014

Sci. Signal.  02 Dec 2014:
Vol. 7, Issue 354, pp. pc31
DOI: 10.1126/scisignal.aaa2963

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Abstract

This Podcast features an interview with Peter Littlefield and Natalia Jura, authors of a Research Article that appears in the 2 December 2014 issue of Science Signaling, abou how mutations in a catalytically inactive tyrosine kinase receptor contribute to cancer. There are four human epidermal growth factor (EGF) receptors—EGFR (also called HER1), HER2, HER3, and HER4. Upon binding to ligands of the EGF family, these receptors form homodimeric or heterodimeric complexes, which, in turn, activates the intracellular kinase domains of the receptors. Whereas EGFR, HER2, and HER4 are catalytically active kinases, HER3 has virtually no catalytic activity, so it can only contribute to signaling as part of heterodimeric complexes with other EGFR family members. Mutations in HER3 are associated with some cancers, and Littlefield et al. investigated how these mutant forms of HER3 stimulate signaling. Structural and biochemical studies showed that HER3 acted as an allosteric activator of EGFR and that cancer-associated mutations in HER3 strengthened the interaction between HER3 and EGFR. These results suggest that interfering with the heterodimerization interface might be a useful strategy for treating cancers in which signaling through the EGFR family is aberrantly activated.

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