title: Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli.
abstract: Recently, we have identified human scribble (hScrib), human homolog of the Drosophila tumor suppressor Scribble, as a substrate of human papillomavirus E6 oncoproteins for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP. Human Scribble, classified as a LAP protein containing leucine-rich repeats and PDZ domains, interacts with E6 through its PDZ domains and C-terminal PDZ domain-binding motif of E6 protein. Interaction between human Discs Large (hDlg), which is a substrate of E6 for the ubiquitin-mediated degradation, and adenomatous polyposis coli (APC) has been shown. Here, we investigated whether hScrib and APC interact with each other in vitro and in vivo. Interaction between hScrib and APC is mediated by the PDZ domains 1 and 4 of hScrib and C-terminal PDZ domain-binding motif of APC. Human Scribble co-localized with APC at the synaptic sites of hippocampal neuron and at the tip of membrane protrusion in the epithelial cell line. Interference of the interaction between hScrib and APC caused disruption of adherens junction. Knockdown of hScrib expression by RNAi disrupts localization of APC at the adherens junction. These data suggest that hScrib may participate in the hDlg-APC complex through its PDZ domains and regulate cell cycle and neural function by associating with APC.
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Takizawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nagasaka
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.forename: Keiichi
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yasugi
authors.forename: Takamasa
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Tadahito
authors.initials: T
authors.lastname: Kanda
authors.forename: Jon M
authors.initials: JM
authors.lastname: Huibregtse
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taketani
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D022005:Adherens Junctions / Q000502:physiology; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D000918:Antibody Specificity; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000502:physiology; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases