Burnham Institute for Medical Research, La Jolla, California

A biologist is gratified to find reconciliation for a conflicted receptor.

When giving talks on the involvement of the Eph family of receptor tyrosine kinases in cancer, I sometimes include a slide of the two-faced Roman god, Janus, to signify the dichotomies of Eph function in cancer cells. Most proteins have a clear-cut function. Some 'moonlighting' proteins carry out two unrelated functions. It is, however, rare for a protein to toggle between opposing activities. The Eph receptors are proving to be such outliers.

High expression of Eph receptors has been correlated with a poor cancer prognosis, but so has Eph silencing. Accordingly, there is good evidence that the Eph receptors can promote as well as inhibit tumour development. In a reconciliation reminiscent of Hegelian synthesis, a recent paper begins to explain how the EphA2 receptor can both promote and inhibit cancer cells' migratory and invasive abilities.

EphA2 activation by ephrin ligands seems to be minimal in most types of cancer cell. Hui Miao and Bingcheng Wang of Case Western Reserve University in Cleveland, Ohio, and their co-workers have shown that the protein Akt — which can be powerfully cancer-promoting — hijacks EphA2 by phosphorylating one of its serine residues, enabling its pro-metastatic activities (H. Miao et al. Cancer Cell 16, 9–20; 2009).

Remarkably, binding by the ephrin-A1 ligand erases this phosphorylation and transforms EphA2 into an anti-invasive molecule.

These findings lead to the counterintuitive proposition that we should encourage rather than inhibit EphA2's ligand-dependent function. It will be interesting to see whether analogous switches convert other Eph receptors between malignant and benign phenotypes.