TY - GEN
T1 - Cbl-phosphatidylinositol 3 kinase interaction differentially regulates macrophage colony-stimulating factor-mediated osteoclast survival and cytoskeletal reorganization
AU - Adapala, Naga Suresh
AU - Barbe, Mary F.
AU - Langdon, Wallace Y.
AU - Tsygankov, Alexander Y.
AU - Sanjay, Archana
PY - 2010/3
Y1 - 2010/3
N2 - 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 CblYF/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 CblYF/YF cultures were unchanged with increasing doses of M-CSF. We found that CblYF/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 CblYF/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.
AB - 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 CblYF/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 CblYF/YF cultures were unchanged with increasing doses of M-CSF. We found that CblYF/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 CblYF/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.
KW - Cbl
KW - M-CSF
KW - Osteoclast
KW - PI3K
KW - Survival
UR - http://www.scopus.com/inward/record.url?scp=77950656187&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950656187&partnerID=8YFLogxK
U2 - 10.1111/j.1749-6632.2009.05346.x
DO - 10.1111/j.1749-6632.2009.05346.x
M3 - Conference contribution
C2 - 20392263
AN - SCOPUS:77950656187
SN - 9781573317856
T3 - Annals of the New York Academy of Sciences
SP - 376
EP - 384
BT - Skeletal Biology and Medicine
PB - Blackwell Publishing Inc.
ER -