DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk.
We examined the mechanism by which M-CSF regulates the cytoskeleton and function of the osteoclast, the exclusive bone resorptive cell. We show that binding of M-CSF to its receptor c-Fms generates a signaling complex comprising phosphorylated DAP12, an adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) and the nonreceptor tyrosine kinase Syk. c-Fms tyrosine 559, the exclusive binding site of c-Src, is necessary for regulation of DAP12/Syk signaling. Deletion of either of these molecules yields osteoclasts that fail to reorganize their cytoskeleton. Retroviral transduction of null precursors with wild-type or mutant DAP12 or Syk reveals that the SH2 domain of Syk and the ITAM tyrosine residues and transmembrane domain of DAP12 mediate M-CSF signaling. Our data provide genetic and biochemical evidence that uncovers an epistatic signaling pathway linking the receptor tyrosine kinase c-Fms to the immune adaptor DAP12 and the cytoskeleton.
Zou
Wei
W
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Reeve
Jennifer L
JL
Liu
Yuli
Y
Teitelbaum
Steven L
SL
Ross
F Patrick
FP
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D003599:Cytoskeleton / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D018909:src Homology Domains
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C484963:Tyrobp protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D016392:Proto-Oncogene Proteins pp60(c-src); D000072377:Syk Kinase; C000606897:Syk protein, mouse