A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation

Ying Xiong, Da Song, Yunfei Cai, Wenfeng Yu, Yee Guide Yeung, E. Richard Stanley

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Receptor tyrosine kinase (RTK) activation involves ligand-induced receptor dimerization and transphosphorylation on tyrosine residues. Colony-stimulating factor-1 (CSF-1)-induced CSF-1 receptor (CSF-1R) tyrosine phosphorylation and ubiquitination were studied in mouse macrophages. Phosphorylation of CSF-1R Tyr-559, required for the binding of Src family kinases (SFKs), was both necessary and sufficient for these responses and for c-Cbl tyrosine phosphorylation and all three responses were inhibited by SFK inhibitors. In c-Cbl-deficient macrophages, CSF-1R ubiquitination and tyrosine phosphorylation were substantially inhibited. Reconstitution with wild-type, but not ubiquitin ligase-defective C381A c-Cbl rescued these responses, while expression of C381A c-Cbl in wild-type macrophages suppressed them. Analysis of site-directed mutations in the CSF-1R further suggests that activated c-Cbl-mediated CSF-1R ubiquitination is required for a conformational change in the major kinase domain that allows amplification of receptor tyrosine phosphorylation and full receptor activation. Thus the results indicate that CSF-1-mediated receptor dimerization leads to a Tyr-559/SFK/c-Cbl pathway resulting in receptor ubiquitination that permits full receptor tyrosine phosphorylation of this class III RTK in macrophages.

Original languageEnglish (US)
Pages (from-to)952-960
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number2
DOIs
StatePublished - Jan 14 2011

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Colony-Stimulating Factor Receptors
Phosphotyrosine
Phosphorylation
Macrophage Colony-Stimulating Factor
Ubiquitination
Macrophage Colony-Stimulating Factor Receptors
Tyrosine
Macrophages
src-Family Kinases
Dimerization
Receptor Protein-Tyrosine Kinases
Chemical activation
Ligases
Ubiquitin
Amplification
tyrosine receptor
Phosphotransferases
Ligands
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation. / Xiong, Ying; Song, Da; Cai, Yunfei; Yu, Wenfeng; Yeung, Yee Guide; Stanley, E. Richard.

In: Journal of Biological Chemistry, Vol. 286, No. 2, 14.01.2011, p. 952-960.

Research output: Contribution to journalArticle

Xiong, Ying ; Song, Da ; Cai, Yunfei ; Yu, Wenfeng ; Yeung, Yee Guide ; Stanley, E. Richard. / A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 2. pp. 952-960.
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