Stepwise receptor activation

10.1083/jcb.1727rr3jcb.1727rr3William A. [email protected] receptor activation T he 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 timeresolved mass spectrometry, to catch events that others have missed. They saw sequential phosphorylations at fi ve 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 signifi cant,” 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 fi rst 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 fi nal outcome. Reference: Furdui, C.M., et al. 2006. Mol. Cell. 21:711–717. 10.1083/jcb.1727r r5jcb.1727r r5William A. Wellswellsw@r ockefeller.eduKinetochore to order