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Sci. Signal., 17 February 2009
Vol. 2, Issue 58, p. ra6
[DOI: 10.1126/scisignal.2000021]


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

Erin D. Lew*, Cristina M. Furdui{dagger}, Karen S. Anderson, and Joseph Schlessinger{ddagger}

Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.

* Present address: Molecular Neurobiology Laboratory, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

{dagger} Present address: Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

Abstract: Autophosphorylation of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1) is mediated by a sequential and precisely ordered three-stage autophosphorylation reaction. First-stage autophosphorylation of an activation loop tyrosine leads to 50- to 100-fold stimulation of kinase activity and is followed by second-stage phosphorylation of three additional tyrosine residues, which are binding sites for signaling molecules. Finally, third-stage phosphorylation of a second activation loop tyrosine leads to an additional 10-fold stimulation of FGFR1 catalytic activity. In this report, we show that sequential autophosphorylation of five tyrosines in the FGFR1 kinase domain is under kinetic control, mediated by both the amino acid sequence surrounding the tyrosines and their locations within the kinase structure, and, moreover, that phosphoryl transfer is the rate-limiting step. Furthermore, the strict order of autophosphorylation is disrupted by a glioblastoma-derived, oncogenic FGFR1 point mutation in the kinase domain. We propose that disrupted stepwise activation of tyrosine autophosphorylation caused by oncogenic and other activating FGFR mutations may lead to aberrant activation of and assembly of signaling molecules by the activated receptor.

{ddagger} To whom correspondence should be addressed. E-mail: joseph.schlessinger{at}

Citation: E. D. Lew, C. M. Furdui, K. S. Anderson, J. Schlessinger, The Precise Sequence of FGF Receptor Autophosphorylation Is Kinetically Driven and Is Disrupted by Oncogenic Mutations. Sci. Signal. 2, ra6 (2009).

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