Treatment of PC12 cells with nerve growth factor induces proteasomal degradation of T-cadherin that requires tyrosine phosphorylation of its cadherin domain
Authors: Shoumei Bai
Samson T Jacob
Jharna Datta
Kalpana Ghoshal
Journal: Journal of Biological Chemistry (2007)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: T-cadherin; cell adhesion; cell signaling; DNA methyltransferase 3b; proteasomal pathway
Affiliations: Department of Molecular and Cellular Biochemistry, College of Medicine, and the., Department of Molecular and Cellular Biochemistry, College of Medicine, and the; Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210. Electronic address: .

Abstract:  T-cadherin (T-Cad), a unique member of the cadherin family of proteins, plays an important role in cell adhesion and cell signaling. Recently, we demonstrated that T-Cad is transcriptionally repressed by DNA methyltransferase 3b during nerve growth factor (NGF)-induced neuronal differentiation of PC12 cells. Here, we show that T-Cad expression is also regulated at the post-translational level by the proteasomal pathway in these cells, which is facilitated upon NGF treatment. Pulse-chase experiments demonstrated that NGF treatment significantly reduced the half-life of T-Cad. Degradation of T-Cad was blocked upon treatment of PC12 cells with the proteasomal inhibitor ZLLL or lactacystin. Ectopic expression of Cdh1 (CDC20 homolog 1), one of the substrate recognition components of anaphase promoting complex (E3 ligase), stimulated T-Cad degradation. Deletion of CD1, one of the five extracellular cadherin domains (CD), promoted degradation of T-Cad, especially in the presence of NGF. On the contrary, deletion of CD2 stabilized this protein maximally. Ubiquitination of different deletion mutants indicates that T-Cad harbors multiple ubiquitination signals. Furthermore, genistein, a protein-tyrosine kinase inhibitor, impeded T-Cad degradation in PC12 cells, implicating requirement of tyrosine phosphorylation in this process. Mutation at tyrosine 327 (Y327F) markedly increased the half-life of T-Cad, suggesting that phosphorylation of this tyrosine residue located within CD2 is critical for this process. These results show that T-cadherin is subject to dual regulation during NGF-induced differentiation of PC12 cells, namely transcriptional repression mediated by Dnmt3b and post-translational degradation through the proteasomal pathway. These data, together with the inhibitory role of T-Cad in neurite outgrowth of PC12 cells upon NGF treatment, underscore the significance of its stringent regulation during this differentiation process. 

Retracted: Yes

PubPeer comments:
 2018 retraction notice. http: www.jbc.org content 293 10 3590  VOLUME 282 (2007) PAGES 27171u201327180 This article has been withdrawn by the authors. In June 2017, the Journal raised questions about Figs. 1B, 2C, 3A, 3C, 3E, 4C, 5A, 5C, 6B, 7A, and 7D. The original data and originally submitted figures were not available for evaluation. The authors were able to locate some data for repeat experiments conducted at the time of the original work, which they state support the conclusions of the paper, and offered to prepare new figures based on that data. However, the Journal declined that offer, a decision with which the authors disagree. The authors state that any errors in the construction of figures in the paper do not alter the scientific conclusions of the work, and they stand by the reproducibility of the experimental data and the conclusions of the paper. u00a9 2018 by The American Society for Biochemistry and Molecular Biology, Inc. , 
 https: retractionwatch.com 2018 03 14 cancer-biologist-retracts-five-papers , 
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 First author appears to currently be affiliated with University of Pittsburgh, and has the unfortunate distinction of appearing as coauthor of multiple papers with similar image concerns while at different institutions: https: pubpeer.com search?q=Shoumei+Bai ![file] ,