Fbxo45 Inhibits Calcium-Sensitive Proteolysis of N-cadherin and Promotes Neuronal Differentiation* [Cell Biology]

August 20th, 2014 by Chung, F.-Z., Sahasrabuddhe, A. A., Ma, K., Chen, X., Basrur, V., Lim, M. S., Elenitoba-Johnson, K. S. J.

Fbxo45 is an atypical E3 ubiquitin ligase which specifically targets proteins for ubiquitin-mediated degradation. Fbxo45 ablation results in defective neuronal differentiation and abnormal formation of neural connections, however the mechanisms underlying these defects are poorly understood. Using an unbiased mass spectrometry-based proteomic screen, we show here that N-cadherin is a novel interactor of Fbxo45. N-cadherin specifically interacts with Fbxo45 through two consensus motifs overlapping the site of calcium-binding and dimerization of the cadherin molecule. N-cadherin interaction with Fbxo45 is significantly abrogated by calcium treatment. Surprisingly, Fbxo45 depletion by RNAi-mediated silencing results in enhanced proteolysis of N-cadherin. Conversely, ectopic expression of Fbxo45 results in decreased proteolysis of N-cadherin. Fbxo45 depletion results in dramatic reduction in N-cadherin expression, impaired neuronal differentiation and diminished formation of neuronal processes. Our studies reveal an unanticipated role for an F-box protein which inhibits proteolysis in the regulation of a critical biological process.