The tight junction protein, occludin, regulates the directional migration of epithelial cells.
Cell polarity proteins regulate tight junction formation and directional migration in epithelial cells. To date, the mechanism by which these polarity proteins assemble at the leading edge of migrating epithelial cells remains unclear. We report that occludin, a transmembrane protein, is localized at the leading edge of migrating cells and regulates directional cell migration. During migration, occludin knockdown disrupted accumulation of aPKC-Par3 and PATJ at the leading edge, and led to a disorganized microtubule network and defective reorientation of the microtubule organization center (MTOC). Phosphorylation of occludin at tyrosine 473 residue allowed recruitment of p85 alpha to the leading edge via association with its C-terminal SH2 domain. Loss of occludin attenuated activation of PI3K, leading to disorganization of the actin cytoskeleton and reduced cell protrusions. Our data indicate that occludin is required for the leading-edge localization of polarity proteins aPKC-Par3 and PATJ and promotes cell protrusion by regulating membrane-localized activation of PI3K.
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Dan
D
Du
Feilai
F
Xu
Lihou
L
Yu
Chenyi
C
Zhang
Xuefeng
X
Lu
Haixin
H
Yuan
Qin
Q
Huang
Fan
F
Zhang
Hongyan
H
Bao
Lianghui
L
Jia
Xunwei
X
Wu
Xueliang
X
Zhu
Xiaohui
X
Zhang
Zhe
Z
Zhang
Zhengjun
Z
Chen
D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology*; D022081:Cell Surface Extensions / Q000502:physiology; D004285:Dogs; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D062793:Occludin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D062725:Tight Junction Proteins; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D016326:Extracellular Matrix Proteins; D008565:Membrane Proteins; D062793:Occludin; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D062725:Tight Junction Proteins; C094556:Ecm1 protein, mouse; C568985:OCLN protein, human; C568986:Ocln protein, mouse; C107903:PATJ protein, human; C115084:Pard3 protein, mouse; C115015:PKC-3 protein