Autophosphorylation of FGFR1 Kinase Is Mediated by a Sequential and Precisely Ordered Reaction
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...
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| Veröffentlicht in: | Molecular cell 2006-03, Vol.21 (5), p.711-717 |
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| container_title | Molecular cell |
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| creator | Furdui, Cristina M. Lew, Erin D. Schlessinger, Joseph Anderson, Karen S. |
| description | 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. |
| doi_str_mv | 10.1016/j.molcel.2006.01.022 |
| format | Article |
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| ispartof | Molecular cell, 2006-03, Vol.21 (5), p.711-717 |
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| language | eng |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Chromatography, Liquid Humans Peptide Fragments - metabolism Phosphorylation Protein Structure, Tertiary PROTEINS Receptor, Fibroblast Growth Factor, Type 1 - chemistry Receptor, Fibroblast Growth Factor, Type 1 - metabolism SIGNALING Spectrometry, Mass, Electrospray Ionization |
| title | Autophosphorylation of FGFR1 Kinase Is Mediated by a Sequential and Precisely Ordered Reaction |
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