Induction of uPA gene expression by the blockage of E‐cadherin via Src‐ and Shc‐dependent Erk signaling

Loss of E‐cadherin‐mediated cell–cell adhesion and expression of proteolytic enzymes characterize the transition from benign lesions to invasive, metastatic tumor, a rate‐limiting step in the progression from adenoma to carcinoma in vivo . A soluble E‐cadherin fragment found recently in the serum and urine of cancer patients has been shown to disrupt cell–cell adhesion and to drive cell invasion in a dominant‐interfering manner. Physical disruption of cell–cell adhesion can be mimicked by the function‐blocking antibody Decma. We have shown previously in MCF7 and T47D cells that urokinase‐type plasminogen activator (uPA) activity is up‐regulated upon disruption of E‐cadherin‐dependent cell–cell adhesion. We explored the underlying molecular mechanisms and found that blockage of E‐cadherin by Decma elicits a signaling pathway downstream of E‐cadherin that leads to Src‐dependent Shc and extracellular regulated kinase (Erk) activation and results in uPA gene activation. siRNA‐mediated knockdown of endogenous Src‐homology collagen protein (Shc) and subsequent expression of single Shc isoforms revealed that p46 Shc and p52 Shc but not p66 Shc were able to mediate Erk activation. A parallel pathway involving PI3K contributed partially to Decma‐induced Erk activation. This report describes that disruption of E‐cadherin‐dependent cell–cell adhesion induces intracellular signaling with the potential to enhance tumorigenesis and, thus, offers new insights into the pathophysiological mechanisms of tumor development.