Classical cadherin cell adhesion receptors are integral membrane proteins that mediate cell-cell interactions, tissue integrity and morphogenesis. Cadherins are best understood to function as membrane-spanning molecular composites that couple adhesion to the cytoskeleton. On the other hand, the membrane lipid environment of the cadherins is an under-investigated aspect of their cell biology. In this review, we discuss two lines of research that show how the membrane can directly or indirectly contribute to cadherin function. Firstly, we consider how modification of its local lipid environment can potentially influence cadherin signalling, adhesion and dynamics, focusing on a role for phosphoinositide-4,5-bisphosphate. Secondly, we discuss how caveolae may indirectly regulate cadherins by modifying either the lipid composition and/or mechanical tension of the plasma membrane. Thus, we suggest that the membrane is a frontier of cadherin biology that is ripe for re-exploration.
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