Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila

Fan Xia, Jinghong Li, Gavin W. Hickey, Amy Tsurumi, Kimberly Larson, Dongdong Guo, Shian Jang Yan, Louis Silver-Morse, Willis X. Li

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

The proto-oncoprotein Raf is pivotal for mitogen-activated protein kinase (MAPK) signaling, and its aberrant activation has been implicated in multiple human cancers. However, the precise molecular mechanism of Raf activation, especially for B-Raf, remains unresolved. By genetic and biochemical studies, we demonstrate that phosphorylation of tyrosine 510 is essential for activation of Drosophila Raf (Draf), which is an ortholog of mammalian B-Raf. Y510 of Draf is phosphorylated by the c-src homolog Src64B. Acidic substitution of Y510 promotes and phenylalanine substitution impairs Draf activation without affecting its enzymatic activity, suggesting that Y510 plays a purely regulatory role. We further show that Y510 regulates Draf activation by affecting the autoinhibitory interaction between the N- and C-terminal fragments of the protein. Finally, we show that Src64B is required for Draf activation in several developmental processes. Together, these results suggest a novel mechanism of Raf activation via Src-mediated tyrosine phosphorylation. Since Y510 is a conserved residue in the kinase domain of all Raf proteins, this mechanism is likely evolutionarily conserved.

Original languageEnglish
Article numbere128
Pages (from-to)1115-1129
Number of pages15
JournalPLoS biology
Volume6
Issue number5
DOIs
Publication statusPublished - 2008 May

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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