The mitogen-activated protein kinase (MAPK) signalling pathway activates many important cell processes, such as proliferation, but how are these signals ever turned off? Madhu Macrae et al. report that downstream gene targets of the pathway, such as the gene encoding the ephrin receptor A2 (EPHA2), mediate a negative feedback loop that is lost in cancer cells.

In a search for MAPK pathway gene targets, Macrae et al. observed that expression of the receptor tyrosine kinase EPHA2 was upregulated fivefold when MAPK signalling was activated. Interestingly, they also found that once EPHA2 is transported to the cell surface, it binds to its ligand, ephrin-A1, and MAPK signalling is downregulated. This seems to be a negative feedback loop that controls MAPK signalling and cell proliferation.

Previous studies had shown that the EPHA2 receptor tyrosine kinase is commonly overexpressed in human cancers, including 40% of breast cancers. So, how can cancer cells express high levels of EPHA2 and maintain signalling along the MAPK pathway? A survey of EPHA2 and its ligand in a panel of 28 breast cancer cell lines revealed that cells that overexpress EPHA2 do not express ephrin-A1 — expression of the receptor and its ligand is mutually exclusive. This is because in addition to upregulating the expression of EPH2A, another outcome of MAPK signalling is downregulation of the ephrin-A1 gene EFNA1.

The authors propose that in normal tissue architecture, one cell type downregulates MAPK signalling and is therefore able to express ephrin-A1, whereas neighbouring cells activate the MAPK signalling pathway and express only the receptor. This interaction between ligand and receptor on adjoining cell types keeps cell proliferation in check. When this structure is lost, such as during tumour formation, EPHA2-expressing cells no longer interact with ephrin-A1 produced by neighbouring cells, resulting in uncontrolled MAPK signalling and proliferation.

In support of this model, the authors showed that ERBB transformation, which is mediated by the MAPK signalling pathway, is suppressed by ephrin-A1 expression in cultured cells. The authors suggest that maintaining normal interactions between ephrin ligands and receptors is an important mechanism of tissue homeostasis that is disrupted during the development of breast and other cancers.