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c-Src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton
Takashi Izawa1, Wei Zou, Jean C Chappel
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Molecular and Cellular Biology
|May 23, 2012
Summary
Receptor activator of nuclear factor kappa-B ligand (RANKL) stimulates osteoclast activity. The tyrosine kinase c-Src links RANK and integrin αvβ3 to organize the osteoclast cytoskeleton, but not osteoclast formation.
Area of Science:
- Cell Biology
- Biochemistry
- Skeletal Biology
Background:
- Receptor activator of nuclear factor kappa-B ligand (RANKL) is known to directly activate osteoclasts, leading to bone resorption.
- The role of c-Src, a key tyrosine kinase involved in cytoskeleton organization, in mediating RANKL-stimulated osteoclast activity was investigated.
Purpose of the Study:
- To determine if c-Src mediates RANKL-stimulated osteoclast activity.
- To elucidate the specific mechanisms by which c-Src interacts with RANK and integrin αvβ3 in osteoclasts.
Main Methods:
- Investigated the association of c-Src with RANK(369-373) in an αvβ3-dependent manner.
- Assessed the role of RANK(369-373) in generating actin rings and activating cytoskeleton-organizing proteins.
- Examined the coprecipitation of αvβ3 and activated RANK in the presence and absence of c-Src.
- Utilized deletion and point mutations in c-Src's SH2 and SH3 domains to study its binding to RANK and αvβ3.
Main Results:
- RANKL induces c-Src to associate with RANK(369-373) in an αvβ3-dependent manner.
- RANK(369-373) is crucial for actin ring formation and cytoskeleton organization, similar to integrin effects.
- c-Src organizes the osteoclast cytoskeleton in response to RANKL but is not involved in osteoclast formation.
- c-Src acts as a linker between activated RANK and αvβ3, with its SH2 domain binding RANK and SH3 domain binding αvβ3.
Conclusions:
- Activated RANK initiates two distinct signaling pathways: one for osteoclast formation and another for cytoskeleton organization.
- c-Src's collaboration with RANK and αvβ3 is essential for organizing the osteoclast cytoskeleton.
- The kinase activity of c-Src, through its SH2 and SH3 domains, mediates the association between RANK and αvβ3, highlighting a novel mechanism in osteoclast biology.
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