title: KIBRA suppresses apical exocytosis through inhibition of aPKC kinase activity in epithelial cells.
abstract: Epithelial cells possess apical-basolateral polarity and form tight junctions (TJs) at the apical-lateral border, separating apical and basolateral membrane domains. The PAR3-aPKC-PAR6 complex plays a central role in TJ formation and apical domain development during tissue morphogenesis. Inactivation and overactivation of aPKC kinase activity disrupts membrane polarity. The mechanism that suppresses active aPKC is unknown. KIBRA, an upstream regulator of the Hippo pathway, regulates tissue size in Drosophila and can bind to aPKC. However, the relationship between KIBRA and the PAR3-aPKC-PAR6 complex remains unknown. We report that KIBRA binds to the PAR3-aPKC-PAR6 complex and localizes at TJs and apical domains in epithelial tissues and cells. The knockdown of KIBRA causes expansion of the apical domain in MDCK three-dimensional cysts and suppresses the formation of apical-containing vacuoles through enhanced de novo apical exocytosis. These phenotypes are restored by inhibition of aPKC. In addition, KIBRA directly inhibits the kinase activity of aPKC in vitro. These results strongly support the notion that KIBRA regulates epithelial cell polarity by suppressing apical exocytosis through direct inhibition of aPKC kinase activity in the PAR3-aPKC-PAR6 complex.
authors.affiliation: Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yoshihama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Horikoshi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hakuno
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005089:Exocytosis; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D019108:Tight Junctions / Q000201:enzymology; D000099293:Protein Kinase C-lambda
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011493:Protein Kinase C; D011506:Proteins; D000099293:Protein Kinase C-lambda; C509689:PARD3 protein, human; C499657:PARD6A protein, human; C513637:WWC1 protein, human