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

نویسندگان

  • Angeles Durán
  • Manuel Serrano
  • Michael Leitges
  • Juana M Flores
  • Sylvain Picard
  • Jacques P Brown
  • Jorge Moscat
  • Maria T Diaz-Meco
چکیده

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.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62.

An increasing number of independent studies indicate that the atypical protein kinase C (PKC) isoforms (aPKCs) are critically involved in the control of cell proliferation and survival. The aPKCs are targets of important lipid mediators such as ceramide and the products of the PI 3-kinase. In addition, the aPKCs have been shown to interact with Ras and with two novel proteins, LIP (lambda-inter...

متن کامل

Mutant p62 Stimulation of Osteoclast Differentiation in Paget’s Disease of Bone

Paget’s disease of the bone (PDB) is an autosomal dominant trait with genetic heterogeneity, characterized by abnormal osteoclastogenesis. Sequestosome 1 (p62) is a scaffold protein that plays an important role in receptor activator of nuclear factor B (RANK) signaling essential for osteoclast (OCL) differentiation. p62 mutation in the ubiquitin-associated (UBA) domain is widely associated with...

متن کامل

Discovering Domains Mediating Protein Interactions

Background: Protein-protein interactions do not provide any direct information re‌garding the domains within the proteins that mediate the interactions. The majority of proteins are multi domain proteins and the interaction between them is often defined by the pairs of their domains. Most of the former studies focus only on interacting do‌main pairs. However they do not consider the in...

متن کامل

The Implication of Androgens in the Presence of Protein Kinase C to Repair Alzheimer’s Disease-Induced Cognitive Dysfunction

Aging, as a major risk factor of memory deficiency, affects neural signaling pathways in hippocampus. In particular, age-dependent androgens deficiency causes cognitive impairments. Several enzymes like protein kinase C (PKC) are involved in memory deficiency. Indeed, PKC regulatory process mediates α-secretase activation to cleave APP in β-amyloid cascade and tau proteins phosphorylation mecha...

متن کامل

Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins.

The Phox and Bem1p (PB1) domain constitutes a recently recognized protein-protein interaction domain found in the atypical protein kinase C (aPKC) isoenzymes, lambda/iota- and zeta PKC; members of mitogen-activated protein kinase (MAPK) modules like MEK5, MEKK2, and MEKK3; and in several scaffold proteins involved in cellular signaling. Among the last group, p62 and Par6 (partitioning-defective...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Developmental cell

دوره 6 2  شماره 

صفحات  -

تاریخ انتشار 2004