title: Fbxo45 inhibits calcium-sensitive proteolysis of N-cadherin and promotes neuronal differentiation.
abstract: 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 that inhibits proteolysis in the regulation of a critical biological process.
authors.affiliation: From the Department of Pathology.
authors.forename: Fu-Zon
authors.initials: FZ
authors.lastname: Chung
authors.affiliation: From the Department of Pathology.
authors.forename: Anagh A
authors.initials: AA
authors.lastname: Sahasrabuddhe
authors.affiliation: From the Department of Pathology.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Ma
authors.affiliation: From the Department of Pathology.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Department of Pathology.
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.affiliation: From the Department of Pathology, the Center for Computational Medicine and Bioinformatics, and.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: From the Department of Pathology, the Center for Computational Medicine and Bioinformatics, and the Protein Folding Diseases Initiative, University of Michigan Medical School, Ann Arbor, Michigan 48109 kojoelen@umich.edu.
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015820:Cadherins; C489083:Cdh2 protein, mouse; D044783:F-Box Proteins; C542381:Fbxo45 protein, mouse; D034741:RNA, Small Interfering; D002118:Calcium
keywords: Calcium; Cell Differentiation; Endocytosis; Intramembrane Proteolysis; Plasma Membrane