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M-CSF regulates the cytoskeleton via recruitment of a multimeric signaling complex to c-Fms Tyr-559/697/721.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2007 Jun 29; Vol. 282 (26), pp. 18991-9. Date of Electronic Publication: 2007 Apr 09. - Publication Year :
- 2007
-
Abstract
- M-CSF is known to induce cytoskeletal reorganization in macrophages and osteoclasts by activation of phosphatidylinositol 3-kinase (PI3K) and c-Src, but the detailed mechanisms remain unclear. We find, unexpectedly, that tyrosine (Tyr) to phenylalanine (Phe) mutation of Tyr-721, the PI3K binding site in the M-CSF receptor c-Fms, fails to suppress cytoskeletal remodeling or actin ring formation. In contrast, mutation of c-Fms Tyr-559 to Phe blocks M-CSF-induced cytoskeletal reorganization by inhibiting formation of a Src Family Kinase SFK.c-Cbl.PI3K complex and the downstream activation of Vav3 and Rac, two key mediators of actin remodeling. Using an add-back approach in which specific Tyr residues are reinserted into c-Fms inactivated by the absence of all seven functionally important Tyr residues, we find that Tyr-559 is necessary but not sufficient to transduce M-CSF-dependent cytoskeletal reorganization. Furthermore, this same add-back approach identifies important roles for Tyr-697 and Tyr-721 in collaborating with Tyr-559 to recruit a multimeric signaling complex that can transduce signals from c-Fms to the actin cytoskeleton.
- Subjects :
- Actin Cytoskeleton metabolism
Amino Acid Substitution
Animals
Cell Movement physiology
Cells, Cultured
Macrophage Colony-Stimulating Factor pharmacology
Macrophages cytology
Mice
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Osteoclasts cytology
Osteoclasts metabolism
Phenylalanine genetics
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation
Protein Structure, Tertiary
Proto-Oncogene Proteins c-cbl metabolism
Receptor, Macrophage Colony-Stimulating Factor chemistry
Receptor, Macrophage Colony-Stimulating Factor genetics
Tyrosine genetics
src-Family Kinases metabolism
Cytoskeleton metabolism
Macrophage Colony-Stimulating Factor metabolism
Macrophages metabolism
Receptor, Macrophage Colony-Stimulating Factor metabolism
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 282
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17420256
- Full Text :
- https://doi.org/10.1074/jbc.M610937200