Three decades after the beginning of the study of the Wnt signaling pathway, major contributions
have been made to elucidate the molecular mechanisms that regulate this signaling pathway and its role in
development, homeostasis and disease. However, there is still a lack of understanding about the relationships
between Wnt signaling and cell-extracellular matrix (ECM) adhesion. Data gathered in the last years is helping
to uncover these relationships. Several ECM proteins are able to regulate components of the Wnt pathway
during development and disease, and their misregulation leads to changes in Wnt signaling. Fibronectin, a
major ECM protein, regulates non-canonical Wnt signaling during embryogenesis in Xenopus and in muscle
regeneration in mouse, whereas it modulates canonical Wnt signaling through modulation of β -catenin.
Integrins, which act as Fibronectin receptors, also modulate Wnt activity, and Syndecan-4, a heparan sulphate
proteoglycan, is able to regulate canonical and non-canonical Wnt pathways, notably during embryogenesis.
Other secreted ECM proteins have been recently associated to the regulation of Wnt signaling, albeit
molecular mechanisms are still unclear. The non-canonical Wnt pathway plays a role in the regulation of the
ECM assembly, and modulates focal adhesion dynamics through the involvement of Wnt components,
whereas Wnt/β-catenin signaling regulates the expression of genes encoding ECM proteins. This evidence
indicates that Wnt signaling and cell-ECM adhesion are two closely related processes, and alterations in this
cross-talk might be involved in disease.