Adhesion integrity activates mechanosensitive proliferative signaling

Weakening of adherens junctions (AJs) and focal adhesions (FAs) adhesiveness has been proposed to enable cancer initiation and progression. Here we report that E-cadherin at cell–cell contacts and vinculin at FAs are transiently under higher tension in MCF10A cells overactivating the Src proto-oncogene. Knockdown of paxillin or P-cadherin, or inhibition of focal adhesion kinase (FAK) or AJ assembly with EGTA, suppresses this force increase across both E-cadherin and vinculin. FAK and P-cadherin trans-homophilic interactions further enhance Src-dependent myosin II and extracellular signal-regulated kinase (ERK) activation. In addition, FAK and P-cadherin potentiate ERK and serum response factor (SRF) signaling, thereby supporting cell proliferation. Furthermore, knockdown of Drosophila cadherin or alpha integrin suppresses Src-induced tissue overgrowth, reinforcing the role of adhesion integrity in Src-driven proliferation. Thus, prior to the loss of cell–cell and cell–matrix adhesiveness, adhesion integrity by P-cadherin at AJs and FAK at FAs could represent a critical step enabling premalignant cells to gain a proliferative advantage.