Research ArticleBiochemistry

The Precise Sequence of FGF Receptor Autophosphorylation Is Kinetically Driven and Is Disrupted by Oncogenic Mutations

Sci. Signal.  17 Feb 2009:
Vol. 2, Issue 58, pp. ra6
DOI: 10.1126/scisignal.2000021

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Is Timing Everything?

Five tyrosine residues in the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1) undergo autophosphorylation, a process that both enhances its kinase activity and provides binding sites for downstream signaling molecules. Lew et al. investigated the mechanisms underlying this sequential and precisely ordered autophosphorylation and determined that it was under kinetic control, with the order of phosphorylation depending on the location of individual tyrosines within the primary and tertiary structures of the FGFR1 kinase domain. Intriguingly, the order in which these tyrosine residues underwent autophosphorylation was disrupted by a glioblastoma-derived, oncogenic FGFR1 point mutation. The authors postulate that such mutations may also alter the temporal recruitment of downstream signaling molecules and this may contribute to their oncogenic activity.

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