Substratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT.

TitleSubstratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT.
Publication TypeJournal Article
Year of Publication2021
AuthorsRabie, EM, Zhang, SX, Dunn, CE, Nelson, CM
JournalMol Biol Cell
Volume32
Issue18
Pagination1664-1676
Date Published2021 08 19
ISSN1939-4586
KeywordsAcrylic Resins, Animals, Breast Neoplasms, Cell Culture Techniques, Epithelial Cells, Epithelial-Mesenchymal Transition, Extracellular Matrix, Female, Focal Adhesions, Integrin beta1, Kinesins, Mammary Glands, Animal, Mice, Protein Serine-Threonine Kinases, Septins, Signal Transduction, Snail Family Transcription Factors, Transforming Growth Factor beta, Tumor Microenvironment
Abstract

<p>Abscission is the final stage of cytokinesis during which the parent cell physically separates to yield two identical daughters. Failure of abscission results in multinucleation (MNC), a sign of genomic instability and a precursor to aneuploidy, enabling characteristics of neoplastic progression. Induction of epithelial-mesenchymal transition (EMT) causes MNC in mammary epithelial cells cultured on stiff microenvironments that have mechanical properties similar to those found in breast tumors, but not on soft microenvironments reminiscent of the normal mammary gland. Here we report that on stiff microenvironments, EMT signaling through Snail up-regulates the midbody-associated proteins septin-6, Mklp1, and anillin, leading to abscission failure and MNC. To uncover the mechanism by which stiff microenvironments promote MNC in cells undergoing EMT, we investigated the role of cell-matrix adhesion through β1-integrin and integrin-linked kinase (ILK). We found that ILK expression, but not kinase activity, is required for EMT-associated MNC in cells on stiff microenvironments. Conversely, increasing focal adhesions by expressing an autoclustering mutant of β1-integrin promotes MNC in cells on soft microenvironments. Our data suggest that signaling through focal adhesions causes failure of cytokinesis in cells actively undergoing EMT. These results highlight the importance of tissue mechanics and adhesion in regulating the cellular response to EMT inducers.</p>

DOI10.1091/mbc.E21-02-0072
Alternate JournalMol Biol Cell
PubMed ID34038147
PubMed Central IDPMC8684726
Grant ListU01 CA214292 / CA / NCI NIH HHS / United States
R01 CA187692 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 HD099030 / HD / NICHD NIH HHS / United States
F30 GM134602 / GM / NIGMS NIH HHS / United States