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Cbl–phosphatidylinositol 3 kinase interaction differentially regulates macrophage colony‐stimulating factor‐mediated osteoclast survival and cytoskeletal reorganization
Author(s) -
Adapala Naga Suresh,
Barbe Mary F.,
Langdon Wallace Y.,
Tsygankov Alexander Y.,
Sanjay Archana
Publication year - 2010
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.05346.x
Subject(s) - microbiology and biotechnology , lamellipodium , phosphatidylinositol , osteoclast , chemistry , macrophage colony stimulating factor , podosome , signal transduction , actin cytoskeleton , cytoskeleton , receptor , biology , macrophage , biochemistry , in vitro , cell
The Cbl protein is a key player in macrophage colony‐stimulating factor (M‐CSF)‐induced signaling. To examine the role of Cbl in M‐CSF‐mediated cellular events, we used Cbl YF/YF knockin mice in which the regulatory tyrosine 737, which when phosphorylated binds to the p85 subunit of phosphatidylinositol 3 kinase (PI3K), is substituted to phenylalanine. In ex vivo cultures, M‐CSF and receptor activator of nuclear factor‐κB ligand‐mediated differentiation of bone marrow precursors from Cbl YF/YF mice generated increased number of osteoclasts; however, osteoclast numbers in Cbl YF/YF cultures were unchanged with increasing doses of M‐CSF. We found that Cbl YF/YF osteoclasts have enhanced intrinsic ability to survive, and this response was further augmented upon exposure to M‐CSF. Treatment of osteoclasts with M‐CSF‐induced actin reorganization and lamellipodia formation in wild‐type osteoclasts; however, in Cbl YF/YF osteoclasts lamellipodia formation was compromised. Collectively, these results indicate that abrogation of the Cbl–PI3K interaction, although not affecting M‐CSF‐induced proliferation and differentiation of precursors, is required for regulation of survival and actin cytoskeletal reorganization of mature osteoclasts.