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Biological Chemistry

Protein Dimer Hints At Anticancer Target

Side-to-side RAF protein dimer's physical contacts, as opposed to phosphorylation, appears to be a causative effect for some cancers

by Sarah Everts
September 7, 2009 | A version of this story appeared in Volume 87, Issue 36

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Credit: Thanashan Rajakulendran
Dimerization of two RAF molecules (purple and gold) is involved in the signaling of some cancers.
Credit: Thanashan Rajakulendran
Dimerization of two RAF molecules (purple and gold) is involved in the signaling of some cancers.

When a cell can no longer rein in its own growth and survival, cancer often follows. The reins are actually controlled by several protein families that sequentially activate one another to initiate cell proliferation. For example, the "unbridled signaling" of a kinase called RAF is to blame for many skin and colon cancers. But the precise mechanism by which this infamous protein is activated has kept researchers guessing. Frank Sicheri of the University of Toronto, Marc Therrien of the University of Montreal, and colleagues are now proposing that RAF is activated when one molecule forms a specific type of "side-to-side" dimer with another RAF molecule (Nature, DOI: 10.1038/nature08314). This activation, caused merely by direct physical contact of the kinase domains, is in contrast to conventional opinion, Sicheri says, which argues that activation of the proteins occurs by mutual phosphorylation. The researchers show that the dimerization is to blame for some cancers, leading them to suggest that disrupting dimer formation would be a good therapeutic target for anticancer drugs.

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