4.8 Article

Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction

Journal

MOLECULAR CELL
Volume 21, Issue 5, Pages 711-717

Publisher

CELL PRESS
DOI: 10.1016/j.molcel.2006.01.022

Keywords

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Funding

  1. NIAMS NIH HHS [R01-AR051448, R01-AR051886] Funding Source: Medline
  2. NIGMS NIH HHS [R01-GM71805] Funding Source: Medline

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Tyrosine phosphorylation of cellular proteins induced by extracellular cues serves as a critical mediator in the control of a great variety of cellular processes. Here, we describe an integrated experimental approach including rapid quench methodology and ESI-LC-MS/MS as well as time-resolved ESI-MS to demonstrate that tyrosine autophosphorylation of the catalytic tyrosine kinase domain of FGF-receptor-1 (FGFR1) is mediated by a sequential and precisely ordered reaction. We also demonstrate that the rate of catalysis of two FGFR substrates is enhanced by 50- to 100-fold after autophosphorylation of Y653 in the activation loop, whereas autophosphorylation of the second site in the activation loop (Y654) results in 500- to 1000-fold increase in the rate of substrate phosphorylation. We propose that FGFR1 is activated by a two-step mechanism mediated by strictly ordered and regulated autophosphorylation, suggesting that distinct phosphorylation states may provide both temporal and spatial resolution to receptor signaling.

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