Macrophage proliferation is regulated through CSF-1 receptor tyrosines 544, 559, and 807

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

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Colony-stimulating factor-1(CSF-1)-stimulated CSF-1 receptor (CSF-1R) tyrosine phosphorylation initiates survival, proliferation, and differentiation signaling pathways in macrophages. Either activation loop Y807F or juxtamembrane domain (JMD) Y559F mutations severely compromise CSF-1-regulated proliferation and differentiation. YEF, a CSF-1R in which all eight tyrosines phosphorylated in the activated receptor were mutated to phenylalanine, lacks in vitro kinase activity and in vivo CSF-1-regulated tyrosine phosphorylation. The addition of Tyr-807 alone to the YEF backbone (Y807AB) led to CSF-1-independent but receptor kinase-dependent proliferation, without detectable activation loop Tyr-807 phosphorylation. The addition of Tyr-559 alone (Y559AB) supported a low level of CSF-1-independent proliferation that was slightly enhanced by CSF-1, indicating that Tyr-559 has a positive Tyr-807-independent effect. Consistent with the postulated autoinhibitory role of the JMD Tyr-559 and its relief by ligand-induced Tyr-559 phosphorylation, the addition of Tyr-559 to the Y807AB background suppressed proliferation in the absence of CSF-1, but restored most of the CSF-1-stimulated proliferation. Full restoration of kinase activation and proliferation required the additional add back of JMD Tyr-544. Inhibitor experiments indicate that the constitutive proliferation of Y807AB macrophages is mediated by the phosphatidylinositol 3-kinase (PI3K) and ERK1/2 pathways, whereas proliferation of WT and Y559,807AB macrophagesis, in addition, contributed to by Src family kinase (SFK)-dependent pathways. Thus Tyr-807 confers sufficient kinase activity for strong CSF-1-independent proliferation, whereas Tyr-559 maintains the receptor in an inactive state. Tyr-559 phosphorylation releases this restraint and may also contribute to the CSF-1- regulated proliferative response by activating Src family kinase.

Original languageEnglish (US)
Pages (from-to)13694-13704
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number17
DOIs
StatePublished - Apr 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yu, W., Chen, J., Xiong, Y., Pixley, F. J., Yeung, Y. G., & Stanley, E. R. (2012). Macrophage proliferation is regulated through CSF-1 receptor tyrosines 544, 559, and 807. Journal of Biological Chemistry, 287(17), 13694-13704. https://doi.org/10.1074/jbc.M112.355610