Truncation of the beta-catenin binding domain of E-cadherin precedes epithelial apoptosis during prostate and mammary involution

A potential target of hormone action during prostate and mammary involution is the intercellular junction of adjacent secretory epithelium. This is su pported by the long-standing observation that one of the first visible stag es of prostate and mammary involution is the disruption of interepithelial adhesion prior to the onset of apoptosis, In a previous study addressing th is aspect of involution, we acquired compelling evidence indicating that th e disruption of E-cadherin-dependent adhesion initiates apoptotic programs during prostate and mammary involution. In cultured prostate and mammary ep ithelial cells, inhibition of E-cadherin-dependent aggregation resulted in cell death following apoptotic stimuli. Loss of cell-cell adhesion in the n onaggregated population appeared to result from the rapid truncation within the cytosolic domain of the mature, 120-kDa species of E-cadherin (E-cad(1 20)). Immunoprecipitations from cell culture and involuting mammary gland d emonstrated that this truncation removed the beta-catenin binding domain fr om the cytoplasmic tail of E-cadherin, resulting in a non beta-catenin bind ing, membrane-bound 97-kDa species (E-cad(97)) and a free cytoplasmic 35-kD a form (E-cad(34)) that is bound to beta-catenin, Examination of E-cadherin expression and cellular distribution during prostate and mammary involutio n revealed a dramatic reduction in junctional membrane staining that correl ated with a similar reduction in E-cad(120) and accumulation of E-cad(97) a nd E-cad(35). The observation that E-cadherin was truncated during involuti on suggested that hormone depletion activated the same apoptotic pathway in vivo as observed in vitro. Based on these findings, we hypothesize that tr uncation of E-cadherin results in the loss of beta-catenin binding and cell ular dissociation that may signal epithelial apoptosis during prostate and mammary involution, Thus, E-cadherin may be central to homeostatic regulati on in these tissues by coordinating adhesion-dependent survival and dissoci ation-induced apoptosis.