Substratum stiffness tunes proliferation downstream of Wnt3a in part by regulating integrin-linked kinase and frizzled-1. Author Siyang Han, Mei-Fong Pang, Celeste Nelson Publication Year 2018 Type Journal Article Abstract 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. Keywords Extracellular Matrix, Humans, Cell Proliferation, Cells, Cultured, Frizzled Receptors, Wnt3A Protein, Protein Serine-Threonine Kinases Journal J Cell Sci Volume 131 Issue 8 Date Published 2018 Apr 23 ISSN Number 1477-9137 DOI 10.1242/jcs.210476 Alternate Journal J Cell Sci PMCID PMC5963841 PMID 29588395 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML