The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival

Naga Suresh Adapala, Mary F. Barbe, Wallace Y. Langdon, Mary C. Nakamura, Alexander Y. Tsygankov, Archana Sanjay

Research output: Contribution to journalArticle

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Abstract

Cbl is an adaptor protein and an E3 ligase that plays both positive and negative roles in several signaling pathways that affect various cellular functions. Tyrosine 737 is unique to Cbl and is phosphorylated by Syk and Src family kinases. Phosphorylated Cbl Tyr737 creates a binding site for the p85 regulatory subunit of PI3K, which also plays an important role in the regulation of bone resorption by osteoclasts. To investigate the role of Cbl-PI3K interaction in bone homeostasis, we examined the knock-in mice (CblYF/YF) in which the PI3K binding site in Cbl is ablated due to the mutation in the regulatory tyrosine. We report that in CblYF/YF mice, despite increased numbers of osteoclasts, bone volume is increased due to defective osteoclast function. Additionally, in ex vivo cultures, mature CblYF/YF osteoclasts showed an increased ability to survive in the presence of RANKL due to delayed onset of apoptosis. RANKL-mediated signaling is perturbed in CblYF/YF osteoclasts, and most interestingly, AKT phosphorylation is up-regulated, suggesting that the lack of PI3K sequestration by Cbl results in increased survival and decreased bone resorption. Cumulatively, these in vivo and in vitro results show that, on one hand, binding of Cbl to PI3K negatively regulates osteoclast differentiation, survival, and signaling events (e.g. AKT phosphorylation), whereas on the other hand it positively influences osteoclast function.

Original languageEnglish (US)
Pages (from-to)36745-36758
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number47
DOIs
StatePublished - Nov 19 2010

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Phosphatidylinositol 3-Kinase
Osteoclasts
Bone Resorption
Bone
Phosphatidylinositol 3-Kinases
Phosphorylation
Tyrosine
Binding Sites
Bone and Bones
Ubiquitin-Protein Ligases
src-Family Kinases
Homeostasis
Apoptosis
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival. / Adapala, Naga Suresh; Barbe, Mary F.; Langdon, Wallace Y.; Nakamura, Mary C.; Tsygankov, Alexander Y.; Sanjay, Archana.

In: Journal of Biological Chemistry, Vol. 285, No. 47, 19.11.2010, p. 36745-36758.

Research output: Contribution to journalArticle

Adapala, Naga Suresh ; Barbe, Mary F. ; Langdon, Wallace Y. ; Nakamura, Mary C. ; Tsygankov, Alexander Y. ; Sanjay, Archana. / The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 47. pp. 36745-36758.
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