BoneKEy Reports | BoneKEy Watch
The molecular basis of cherubism
DOI:10.1038/bonekey.2012.31
People with the autosomal dominant hereditary syndrome cherubism have mutations in Sh3bp2, the gene that codes for the adaptor protein 3BP2. They have abnormal facial bones due to inflammation and bone destruction, and have tooth and eye problems because of the impact of inflammation on the jaw and eye socket. The molecular basis of these manifestations has now been investigated in a mouse model of the disease.
Levaot et al. used a mouse model of cherubism to show that tankyrase, a member of the PARP family, is the regulator of 3BP2 stability. In osteoclasts, tankyrase represses 3BP2 protein levels through ADP-ribosylation and subsequent ubiquitylation by the E3-ubiquitin ligase RNF146. The mutations in tankyrase that cause cherubism stabilize 3BP2, increasing its capability to drive osteoclast differentiation, a key feature of the disease.
The findings may also have relevance to carcinogenesis, as loss of function of tankyrase and significantly increased 3BP2 expression can contribute to the highly active SRC observed in some human cancers.
Editor's comment: Tankyrase, a previously unknown contributor to bone homeostasis, is revealed as a negative regulator of the SRC signaling pathway through action on 3BP2. This not only sheds light on the molecular basis of cherubism, it suggests that SRC kinase inhibitors may be therapeutically beneficial for people affected by the condition.
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