Loss of Tankyrase-mediated Destruction of 3BP2 is the Underlying Pathogenic Mechanism of Cherubism

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Dec 14

PMID 22153076

Citations 102

Authors

Noam Levaot

Oleksandr Voytyuk

Ioannis Dimitriou

Fabrice Sircoulomb

Arun Chandrakumar

Marcel Deckert

Paul M Krzyzanowski

Andrew Scotter

Shengqing Gu

Salima Janmohamed

Feng Cong

Paul D Simoncic

Yasuyoshi Ueki

Jose La Rose

Robert Rottapel

Affiliations

Soon will be listed here.

Abstract

Cherubism is an autosomal-dominant syndrome characterized by inflammatory destructive bony lesions resulting in symmetrical deformities of the facial bones. Cherubism is caused by mutations in Sh3bp2, the gene that encodes the adaptor protein 3BP2. Most identified mutations in 3BP2 lie within the peptide sequence RSPPDG. A mouse model of cherubism develops hyperactive bone-remodeling osteoclasts and systemic inflammation characterized by expansion of the myelomonocytic lineage. The mechanism by which cherubism mutations alter 3BP2 function has remained obscure. Here we show that Tankyrase, a member of the poly(ADP-ribose)polymerase (PARP) family, regulates 3BP2 stability through ADP-ribosylation and subsequent ubiquitylation by the E3-ubiquitin ligase RNF146 in osteoclasts. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the SRC, SYK, and VAV signaling pathways.

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