A novel role of Rac1 GTPase in JCV T-antigen-mediated beta-catenin stabilization.
Wnt signaling follows canonical and non-canonical pathways to regulate a variety of processes during cellular homeostasis and development. The large T-antigen (T-Ag) of the human neurotropic JC virus, has been shown to modulate the Wnt-signaling pathway via interaction with beta-catenin, one of the most important components of the canonical Wnt pathway. Here, we have identified an alternative non-canonical pathway that allows T-Ag to recruit Rac1 for stabilizing beta-catenin by inhibiting its ubiquitin-dependent proteasomal degradation. We demonstrate that inhibition of Rac1 by its dominant negative mutant, RacN17, abrogates T-Ag-mediated stabilization of beta-catenin yet exhibits no impact on the transcriptional activity of beta-catenin. Results from immunocytochemistry revealed that together with T-Ag, a pool of beta-catenin appears at the cell surface, particularly at the membrane ruffles where active Rac1 is positioned. Interestingly, cooperativity between T-Ag and beta-catenin leads to activation of Rac1, which in turn, stimulates its association with beta-catenin. These observations unravel the interplay between beta-catenin and Rac1 that is initiated by T-Ag and results in stabilization of beta-catenin and its presence in cell membrane ruffles.
Bhattacharyya
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Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19122, USA.
Noch
E K
EK
Khalili
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K
D000957:Antigens, Viral, Tumor / Q000032:analysis / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007577:JC Virus; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; D025801:Ubiquitin; D051153:Wnt Proteins; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex; D020830:rac1 GTP-Binding Protein