Induced cortical tension restores functional junctions in adhesion-defective carcinoma cells

Shoko Ito; Satoru Okuda; Masako Abe; Mari Fujimoto; Tetsuo Onuki; Tamako Nishimura; Masatoshi Takeichi

doi:10.1038/s41467-017-01945-y

Induced cortical tension restores functional junctions in adhesion-defective carcinoma cells

Nat Commun. 2017 Nov 28;8(1):1834. doi: 10.1038/s41467-017-01945-y.

Authors

Shoko Ito¹, Satoru Okuda², Masako Abe³, Mari Fujimoto³, Tetsuo Onuki³, Tamako Nishimura^{1

4}, Masatoshi Takeichi⁵

Affiliations

¹ Laboratory for Cell Adhesion and Tissue Patterning, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
² Laboratoty for In Vitro Histogenesis, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
³ Seed Compounds Exploratory Unit for Drug Discovery Platform, Drug Discovery Platforms Cooperation Division, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, 351-0198, Japan.
⁴ Nara Institute of Science and Technology, Ikoma, 630-0192, Japan.
⁵ Laboratory for Cell Adhesion and Tissue Patterning, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan. takeichi@cdb.riken.jp.

Abstract

Normal epithelial cells are stably connected to each other via the apical junctional complex (AJC). AJCs, however, tend to be disrupted during tumor progression, and this process is implicated in cancer dissemination. Here, using colon carcinoma cells that fail to form AJCs, we investigated molecular defects behind this failure through a search for chemical compounds that could restore AJCs, and found that microtubule-polymerization inhibitors (MTIs) were effective. MTIs activated GEF-H1/RhoA signaling, causing actomyosin contraction at the apical cortex. This contraction transmitted force to the cadherin-catenin complex, resulting in a mechanosensitive recruitment of vinculin to cell junctions. This process, in turn, recruited PDZ-RhoGEF to the junctions, leading to the RhoA/ROCK/LIM kinase/cofilin-dependent stabilization of the junctions. RhoGAP depletion mimicked these MTI-mediated processes. Cells that normally organize AJCs did not show such MTI/RhoA sensitivity. Thus, advanced carcinoma cells require elevated RhoA activity for establishing robust junctions, which triggers tension-sensitive reorganization of actin/adhesion regulators.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton / metabolism
Actin Cytoskeleton / ultrastructure
Actin Depolymerizing Factors / metabolism
Actins / metabolism
Actomyosin / metabolism
Adherens Junctions / metabolism*
Adherens Junctions / ultrastructure
Biomechanical Phenomena
Caco-2 Cells
Cadherins / metabolism
Cell Adhesion / physiology*
Cell Adhesion Molecules / metabolism*
Cell Line, Tumor
Colonic Neoplasms / metabolism*
Colonic Neoplasms / pathology
Cytoskeletal Proteins / metabolism*
Epithelial Cells / metabolism
Guanine Nucleotide Exchange Factors / metabolism
HT29 Cells / cytology
HT29 Cells / drug effects
HT29 Cells / physiology*
Humans
Intercellular Junctions / physiology*
Lim Kinases / metabolism
Microtubules
Myosin Type II / metabolism
Nocodazole / pharmacology
Signal Transduction
Vinculin / metabolism
rho-Associated Kinases / metabolism
rhoA GTP-Binding Protein / metabolism

Substances

Actin Depolymerizing Factors
Actins
Cadherins
Cell Adhesion Molecules
Cytoskeletal Proteins
Guanine Nucleotide Exchange Factors
VCL protein, human
Vinculin
Actomyosin
LIMK1 protein, human
Lim Kinases
rho-Associated Kinases
Myosin Type II
rhoA GTP-Binding Protein
Nocodazole