DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk

Mol Cell. 2008 Aug 8;31(3):422-31. doi: 10.1016/j.molcel.2008.06.023.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Animals
  • Cytoskeleton / drug effects
  • Cytoskeleton / enzymology*
  • Enzyme Activation / drug effects
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Mice
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / enzymology*
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism*
  • Signal Transduction / drug effects
  • Syk Kinase
  • src Homology Domains

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Tyrobp protein, mouse
  • Macrophage Colony-Stimulating Factor
  • Protein-Tyrosine Kinases
  • Receptor, Macrophage Colony-Stimulating Factor
  • Proto-Oncogene Proteins pp60(c-src)
  • Syk Kinase
  • Syk protein, mouse