Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain

Yoshihiro Kobashigawa, Shinjiro Amano, Mariko Yokogawa, Hiroyuki Kumeta, Hiroshi Morioka, Masayori Inouye, Joseph Schlessinger, Fuyuhiko Inagaki

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Abstract

Receptor and nonreceptor tyrosine kinases are enzymes that play important roles in regulating signal transduction pathways in a variety of normal cellular process and in many pathological conditions. Ordered phosphorylation is required for receptor tyrosine kinase (RTK) activation, a process mediated by transient dimer formation of the kinase domains. This process is triggered by the tyrosine phosphorylation in the activation loop. Here, we report structural and biochemical analyses of the tyrosine kinase domain interaction of fibroblast growth factor receptor 1 (FGFR1) required for the initial phosphorylation step. On the basis of nuclear magnetic resonance (NMR) analysis and covalent cross-linking experiments, we propose a parallel symmetric dimer model where specific contacts are formed between the N-lobes and C-lobes, respectively, in the FGFR1 kinase domains. Moreover, assignment of the contact sites between two FGFR1 kinase domains are supported by a trans-phosphorylation assay and by mutational analyses. The present report shows the molecular mechanism underlying the control of trans-phosphorylation of a critical auto-regulatory site in FGF receptors' catalytic domain.

Original languageEnglish (US)
Pages (from-to)860-870
Number of pages11
JournalGenes to Cells
Volume20
Issue number10
DOIs
StatePublished - Oct 2015

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All Science Journal Classification (ASJC) codes

  • Genetics
  • Cell Biology

Cite this

Kobashigawa, Y., Amano, S., Yokogawa, M., Kumeta, H., Morioka, H., Inouye, M., Schlessinger, J., & Inagaki, F. (2015). Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain. Genes to Cells, 20(10), 860-870. https://doi.org/10.1111/gtc.12277