Substratum stiffness tunes proliferation downstream of Wnt3a in part by regulating integrin-linked kinase and frizzled-1.

TitleSubstratum stiffness tunes proliferation downstream of Wnt3a in part by regulating integrin-linked kinase and frizzled-1.
Publication TypeJournal Article
Year of Publication2018
AuthorsHan, S, Pang, M-F, Nelson, CM
JournalJ Cell Sci
Volume131
Issue8
Date Published2018 04 23
ISSN1477-9137
KeywordsCell Proliferation, Cells, Cultured, Extracellular Matrix, Frizzled Receptors, Humans, Protein-Serine-Threonine Kinases, Wnt3A Protein
Abstract

<p>The Wnt/β-catenin pathway controls a variety of cellular behaviors, aberrant activation of which are associated with tumor progression in several types of cancer. The same cellular behaviors are also affected by the mechanical properties of the extracellular matrix (ECM) substratum, which induces signaling through integrins and integrin-linked kinase (ILK). Here, we examined the role of substratum stiffness in the regulation of cell proliferation downstream of Wnt3a. We found that treatment with Wnt3a increased proliferation of cells cultured on stiff substrata, with compliances characteristic of breast tumors, but not of cells on soft substrata, with compliances comparable to that of normal mammary tissue. Depleting ILK rendered cells unresponsive to Wnt3a on both substrata. Ectopic expression of ILK permitted Wnt3a to induce proliferation of cells on both microenvironments, although proliferation on soft substrata remained lower than that on stiff substrata. We further showed that ILK regulates expression of the Wnt receptor frizzled-1 (), suggesting the presence of a positive feedback loop between Wnt3a, ILK and Fzd1. These findings suggest that tissue mechanics regulates the cellular response to Wnt under physiological and pathological microenvironmental conditions.This article has an associated First Person interview with the first author of the paper.</p>

DOI10.1242/jcs.210476
Alternate JournalJ Cell Sci
PubMed ID29588395
PubMed Central IDPMC5963841
Grant ListU01 CA214292 / CA / NCI NIH HHS / United States
R21 HL110335 / HL / NHLBI NIH HHS / United States
R01 CA187692 / CA / NCI NIH HHS / United States
R21 HL118532 / HL / NHLBI NIH HHS / United States
R01 HL120142 / HL / NHLBI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States