Dataset Information


Phosphorylation of CSF-1R Y721 mediates its association with PI3K to regulate macrophage motility and enhancement of tumor cell invasion.

ABSTRACT: Colony stimulating factor-1 (CSF-1) regulates macrophage morphology and motility, as well as mononuclear phagocytic cell proliferation and differentiation. The CSF-1 receptor (CSF-1R) transduces these pleiotropic signals through autophosphorylation of eight intracellular tyrosine residues. We have used a novel bone-marrow-derived macrophage cell line system to examine specific signaling pathways activated by tyrosine-phosphorylated CSF-1R in macrophages. Screening of macrophages expressing a single species of CSF-1R with individual tyrosine-to-phenylalanine residue mutations revealed striking morphological alterations upon mutation of Y721. M?/?.Y721F cells were apolar and ruffled poorly in response to CSF-1. Y721-P-mediated CSF-1R signaling regulated adhesion and actin polymerization to control macrophage spreading and motility. Moreover, the reduced motility of M?/?.Y721F macrophages was associated with their reduced capacity to enhance carcinoma cell invasion. Y721 phosphorylation mediated the direct association of the p85 subunit of phosphoinositide 3-kinase (PI3K) with the CSF-1R, but not that of phospholipase C (PLC) ?2, and induced polarized PtdIns(3,4,5)P? production at the putative leading edge, implicating PI3K as a major regulator of CSF-1-induced macrophage motility. The Y721-P-motif-based motility signaling was at least partially independent of both Akt and increased Rac and Cdc42 activation but mediated the rapid and transient association of an unidentified ~170 kDa phosphorylated protein with either Rac-GTP or Cdc42-GTP. These studies identify CSF-1R-Y721-P-PI3K signaling as a major pathway in CSF-1-regulated macrophage motility and provide a starting point for the discovery of the immediate downstream signaling events.


PROVIDER: S-EPMC3104034 | BioStudies | 2011-01-01

REPOSITORIES: biostudies

Similar Datasets

2014-10-23 | E-GEOD-62630 | BioStudies
2008-01-01 | S-EPMC2516905 | BioStudies
2014-10-23 | E-GEOD-62630 | ArrayExpress
2016-01-01 | S-EPMC5045265 | BioStudies
2015-01-01 | S-EPMC4335087 | BioStudies
1000-01-01 | S-EPMC1800684 | BioStudies
2014-01-01 | S-EPMC4141303 | BioStudies
1000-01-01 | S-EPMC2924605 | BioStudies
2016-05-20 | GSE80399 | GEO
2012-01-01 | S-EPMC3251714 | BioStudies