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 supported by the long-standing observation that one of the first visible stages of prostate and mammary involution is the disruption of interepithelial adhesion prior to the onset of apoptosis. In a previous study addressing this aspect of involution, we acquired compelling evidence indicating that the disruption of E-cadherin-dependent adhesion initiates apoptotic programs during prostate and mammary involution. In cultured prostate and mammary epithelial cells, inhibition of E-cadherin-dependent aggregation resulted in cell death following apoptotic stimuli. Loss of cell-cell adhesion in the nonaggregated population appeared to result from the rapid truncation within the cytosolic domain of the mature, 120-kDa species of E-cadherin (E-cad(120)). Immunoprecipitations from cell culture and involuting mammary gland demonstrated that this truncation removed the beta-catenin binding domain from the cytoplasmic tail of E-cadherin, resulting in a non-beta-catenin binding, membrane-bound 97-kDa species (E-cad(97)) and a free cytoplasmic 35-kDa form (E-cad(35)) that is bound to beta-catenin. Examination of E-cadherin expression and cellular distribution during prostate and mammary involution revealed a dramatic reduction in junctional membrane staining that correlated with a similar reduction in E-cad(120) and accumulation of E-cad(97) and E-cad(35). The observation that E-cadherin was truncated during involution suggested that hormone depletion activated the same apoptotic pathway in vivo as observed in vitro. Based on these findings, we hypothesize that truncation of E-cadherin results in the loss of beta-catenin binding and cellular dissociation that may signal epithelial apoptosis during prostate and mammary involution. Thus, E-cadherin may be central to homeostatic regulation in these tissues by coordinating adhesion-dependent survival and dissociation-induced apoptosis.
Vallorosi
C J
CJ
Department of Surgery, Division of Urology, University of Michigan Ann Arbor, Ann Arbor, Michigan 48109, USA.
Day
K C
KC
Zhao
X
X
Rashid
M G
MG
Rubin
M A
MA
Johnson
K R
KR
Wheelock
M J
MJ
Day
M L
ML
D017209:Apoptosis; D001665:Binding Sites; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D015534:Trans-Activators; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin