Cbl-phosphatidylinositol 3 kinase interaction differentially regulates macrophage colony-stimulating factor-mediated osteoclast survival and cytoskeletal reorganization.
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-kappaB 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.
Adapala
Naga Suresh
NS
Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA, USA.
Barbe
Mary F
MF
Langdon
Wallace Y
WY
Tsygankov
Alexander Y
AY
Sanjay
Archana
A
D000818:Animals; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050722:Oncogene Protein v-cbl / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D003115:Colony-Stimulating Factors; D050722:Oncogene Protein v-cbl; D019869:Phosphatidylinositol 3-Kinases