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The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis.

The atypical PKCs (aPKCs) have been implicated genetically in at least two independent signaling cascades that control NF-kappa B and cell polarity, through the interaction with the adapters p62 and Par-6, respectively. P62 binds TRAF6, which plays an essential role in osteoclastogenesis and bone remodeling. Recently, p62 mutations have been shown to be the cause of the 5q35-linked Paget's disease of bone, a genetic disorder characterized by aberrant osteoclastic activity. Here we show that p62, like TRAF6, is upregulated during RANK-L-induced osteoclastogenesis and that the genetic inactivation of p62 in mice leads to impaired osteoclastogenesis in vitro and in vivo, as well as inhibition of IKK activation and NF-kappa B nuclear translocation. In addition, RANK-L stimulation leads to the inducible formation of a ternary complex involving TRAF6, p62, and the aPKCs. These observations demonstrate that p62 is an important mediator during osteoclastogenesis and induced bone remodeling.

Pubmed ID: 14960283


  • DurĂ¡n A
  • Serrano M
  • Leitges M
  • Flores JM
  • Picard S
  • Brown JP
  • Moscat J
  • Diaz-Meco MT


Developmental cell

Publication Data

February 12, 2004

Associated Grants


Mesh Terms

  • Animals
  • Blotting, Southern
  • Bone Marrow
  • Bone Remodeling
  • Bone Resorption
  • Carrier Proteins
  • Cell Count
  • Cells, Cultured
  • Electrophoretic Mobility Shift Assay
  • Embryo, Mammalian
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts
  • Gene Expression
  • Glycoproteins
  • Hematoxylin
  • I-kappa B Kinase
  • Immediate-Early Proteins
  • Immunoblotting
  • Interleukin-6
  • Macrophage Colony-Stimulating Factor
  • Macrophages
  • Mice
  • Mice, Knockout
  • NF-kappa B
  • Osteoclasts
  • Osteogenesis
  • Osteoprotegerin
  • Parathyroid Hormone-Related Protein
  • Precipitin Tests
  • Protein Kinase C
  • Protein Kinase C-epsilon
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 6
  • Time Factors
  • Transcription Factors