CSF-1 receptor structure/function in MacCsf1r-/-macrophages: Regulation of proliferation, differentiation, and morphology

Wenfeng Yu, Jian Chen, Ying Xiong, Fiona J. Pixley, Xu Ming Dai, Yee Guide Yeung, E. Richard Stanley

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

CSF-1 is the major regulator of tissue macrophage development and function. A GM-CSF-dependent, CSF-1 receptor (CSF-1R)-deficient F4/80hiMac- 1+Gr1-CD11c+ bone marrow macrophage (BMM) line (MacCsf1r-/-) was developed to study the roles of the eight intracellular CSF-1R tyrosines phosphorylated upon receptor activation. Retroviral expression of the wild-type CSF-1R rescued the CSF-1-induced survival, proliferation, differentiation, and morphological characteristics of primary BMM. Mutation of all eight tyrosines failed to rescue, whereas the individual Y → F mutants (544, 559, 697, 706, 721, 807, 921, 974) rescued these CSF-1-inducible phenotypes to varying degrees. The juxtamembrane domain Y559F and activation loop Y807F mutations severely compromised proliferation and differentiation, whereas Y706, Y721F, and Y974F mutations altered morphological responses, and Y706F increased differentiation. Despite their retention of significant in vitro tyrosine kinase activity, Y559F and Y807F mutants exhibited severely impaired in vivo receptor tyrosine phosphorylation, consistent with the existence of cellular mechanisms inhibiting CSF-1R tyrosine phosphorylation that are relieved by phosphorylation of these two sites. The MacCsf1r-/- macrophage line will facilitate genetic and proteomic approaches to CSF-1R structure/function studies in the major disease-related CSF-1R-expressing cell type.

Original languageEnglish (US)
Pages (from-to)852-863
Number of pages12
JournalJournal of Leukocyte Biology
Volume84
Issue number3
DOIs
StatePublished - Sep 1 2008

Keywords

  • Hematopoietic growth factor
  • Receptor tyrosine kinase mutations
  • Tyrosine kinase
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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