Tumour development actors ERK1 and ERK2 found to play opposite roles

The proteins ERK1 and ERK2 may play opposite roles during tumour development. A study published today in the open access journal Journal of Biology shows that the phosphorylating enzyme, or 'kinase', ERK1 can inhibit cell proliferation by interfering with the action of the related kinase ERK2. ERK1 and ERK2 are crucial components of the signalling cascade that mediates the function of the Ras oncogenes, an important class of oncogenes involved in the development of many human cancers. In the absence of ERK1, ERK2 shows increased activity and it promotes both normal and Ras-dependent cell proliferation. In contrast, increased levels of ERK1 in cells significantly slow down their proliferation rate, especially when Ras oncoproteins are activated. These findings disprove the assumption that ERK1 and ERK2 have the same function and are fully interchangeable. This suggests that the mechanism controlling cell proliferation and malignancy is more complex than previously thought.

Chiara Vantaggiato, Ivan Formentini and colleagues in Riccardo Brambilla's group, from the San Raffaele Scientific Institute in Milan, Italy, used gene targeting and RNA interference (RNAi) techniques to inhibit the MAP kinases ERK1 and ERK2 in mouse cells. Their results show that inhibiting ERK1 enhances ERK2 activity and promotes cell proliferation. In contrast, the knockdown of ERK2 almost completely abolishes cell proliferation. Mouse tumour cells expressing ERK1, but not ERK2, to higher levels than normally seen in tumour cells, grow into very small tumours when transplanted into live mice. Cells expressing only the protein Ras grow into much larger tumours and overexpressing ERK2 doesn't affect the size of the tumours.

The authors propose that ERK1 and ERK2 are in competition to bind to other regulatory molecules in the signalling pathway. Their activities and expression levels must be finely tuned to ensure normal cell proliferation.

Article:
ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially
Chiara Vantaggiato, Ivan Formentini, Attilio Bondanza, Chiara Bonini, Luigi Naldini and Riccardo Brambilla
Journal of Biology 2006, 5:14 (to be published 28 June 2006)

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