title: Cbl-phosphatidylinositol 3 kinase interaction differentially regulates macrophage colony-stimulating factor-mediated osteoclast survival and cytoskeletal reorganization.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Naga Suresh
authors.initials: NS
authors.lastname: Adapala
authors.forename: Mary F
authors.initials: MF
authors.lastname: Barbe
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Tsygankov
authors.forename: Archana
authors.initials: A
authors.lastname: Sanjay
mesh_terms: 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
chemical_list: D003115:Colony-Stimulating Factors; D050722:Oncogene Protein v-cbl; D019869:Phosphatidylinositol 3-Kinases