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Raf-1 sheds then spreads its inhibitions

Cells lacking Raf-1 contract due to Rok- overactivation (left). Raf-1's regulatory domain inhibits Rok- and restores normal cell shape (right).

The regulatory domain of the kinase Raf-1 switches from inhibiting its own protein's activity to blocking a different kinase in a separate signaling pathway, say Niault et al., uncovering a novel type of signaling cross talk.

Raf-1 and Rok- are two kinases, activated respectively by the small GTPases Ras and Rho. Before their activation, both kinases keep themselves quiet through intramolecular interactions between their inhibitory regions and catalytic domains. Activated Raf-1 also keeps Rok- in check to promote cell migration, survival, and tumorigenesis—the inhibition of Rok- by Raf-1 is essential for the development and maintenance of Ras-induced epidermal tumors. But how this cross talk occurs is unclear.

Niault et al. found that when both kinases are activated by their GTPases, the regulatory domain of Raf-1 binds directly to the Rok- kinase region to attenuate its activity. Cells lacking Raf-1 are abnormally shaped, migrate more slowly, and are more sensitive to cell death due to Rok- overactivation, but the reintroduction of the Raf-1 regulatory domain alone reversed these phenotypes by blocking Rok- function.

The inhibition of one kinase by another through direct binding is a new kind of regulation, says senior author Manuela Baccarini—cross talk between kinases and different signaling pathways is usually achieved through phosphorylation. Given the interaction's importance in cancer progression, Baccarini now wants to develop molecules that block the inhibitory association, and test these in animal tumor models.

References

Niault, T., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200906178.[Abstract/Free Full Text]

bshort{at}rockefeller.edu

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This Article Full Text (PDF, 494K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Short, B. PubMed Articles by Short, B. Social Bookmarking                            What's this?