Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli.
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.
Takizawa
Shin
S
Department of Obstetrics and Gynecology, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.
Nagasaka
Kazunori
K
Nakagawa
Shunsuke
S
Yano
Tetsu
T
Nakagawa
Keiichi
K
Yasugi
Toshiharu
T
Takeuchi
Takamasa
T
Kanda
Tadahito
T
Huibregtse
Jon M
JM
Akiyama
Tetsu
T
Taketani
Yuji
Y
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*
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