|Title||Substratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Rabie, EM, Zhang, SX, Dunn, CE, Nelson, CM|
|Journal||Mol Biol Cell|
|Date Published||2021 May 26|
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, a sign of genomic instability and a precursor to aneuploidy, enabling characteristics of neoplastic progression. Induction of epithelial-mesenchymal transition (EMT) causes multinucleation 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 upregulates the midbody-associated proteins septin-6, Mklp1, and anillin, leading to abscission failure and multinucleation. To uncover the mechanism by which stiff microenvironments promote multinucleation 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 multinucleation in cells on stiff microenvironments. Conversely, increasing focal adhesions by expressing an autoclustering β1-integrin promotes multinucleation 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.
|Alternate Journal||Mol Biol Cell|