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Stepwise receptor activation

Five phosphorylations of the FGF receptor occur in a strict order. ANDERSON

The FGF receptor gets its multiple phosphorylations not randomly but in a strictly ordered sequence, say Cristina Furdul, Erin Lew, Joseph Schlessinger, and Karen Anderson (Yale University, New Haven, CT). The intermediate phosphorylation states—neither fully off nor fully on—may act as members of a carefully controlled activation and recruitment pathway.

The Yale group relied on rapid reaction techniques, including time-resolved mass spectrometry, to catch events that others have missed. They saw sequential phosphorylations at five sites, with an invariant order of phosphorylation. For example, every triphosphorylated receptor had the same 3 sites phosphorylated.

"The fact that it's so precise, without any redundancy, suggests it's significant," says Schlessinger. The mechanism for ordering is not yet known, but one possibility is that phosphorylation at each site simply has different kinetics.

One consequence is a stepwise activation of catalysis rate. The first phosphorylation increased the receptor's catalysis rate 50–100-fold; the last increased it a further 10-fold.

In addition, each state "will have a lower or higher propensity to activate different pathways," says Anderson. She speculates that other tyrosine kinase receptors that look similar may turn out to have very different activation sequences. "That order could control the time when each downstream signaling module is activated," says Anderson. The different activation times may in turn change the way that the signaling pathways interact, thus producing a different final outcome.

Reference:

Furdui, C.M., et al. 2006. Mol. Cell. 21:711–717.[CrossRef][Medline]

William A. Wells

wellsw{at}rockefeller.edu

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This Article Full Text (PDF, 1137K) 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 Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                            What's this?