M-CSF regulates the cytoskeleton via recruitment of a multimeric signaling complex to c-Fms Tyr-559/697/721.

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.
Mesh Terms:
Actin Cytoskeleton, Amino Acid Substitution, Animals, Cell Movement, Cells, Cultured, Cytoskeleton, Macrophage Colony-Stimulating Factor, Macrophages, Mice, Mice, Inbred C57BL, Mutagenesis, Site-Directed, Osteoclasts, Phenylalanine, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Structure, Tertiary, Proto-Oncogene Proteins c-cbl, Receptor, Macrophage Colony-Stimulating Factor, Signal Transduction, Tyrosine, src-Family Kinases
J. Biol. Chem.
Date: Jun. 29, 2007
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