Lysosomal targeting of E-cadherin: a unique mechanism for the down-regulation of cell-cell adhesion during epithelial to mesenchymal transitions.
A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms. Here we demonstrate that, upon v-Src expression, a potent trigger of epithelial to mesenchymal transitions, E-cadherin is internalized and then shuttled to the lysosome instead of being recycled back to the lateral membrane. Thus, while E-cadherin internalization facilitates the dissolution of adherens junctions, its subsequent traffic to the lysosome serves as a means to ensure that cells do not reform their cell-cell contacts and remain motile. We also show that ubiquitin tagging of E-cadherin is essential for its sorting to the lysosome. The lysosomal targeting of E-cadherin is mediated by hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and v-Src-induced activation of the Rab5 and Rab7 GTPases. Our studies reveal that the lysosomal targeting of E-cadherin is an important posttranscriptional mechanism to deplete cellular E-cadherin during Src-induced epithelial to mesenchymal transitions.
Palacios
Felipe
F
Department of Biological Sciences, University of Notre Dame, Box 369, Galvin Life Sciences Bldg., Notre Dame, IN 46556-0369, USA.
Tushir
Jogender S
JS
Fujita
Yasuyuki
Y
D'Souza-Schorey
Crislyn
C
D000818:Animals; D001692:Biological Transport; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D002450:Cell Communication; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D004285:Dogs; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D047468:Immunoprecipitation; D008247:Lysosomes / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012190:Retroviridae / Q000235:genetics; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins; D019061:src-Family Kinases / Q000378:metabolism
D015820:Cadherins; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D025801:Ubiquitin; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D000090802:rab7 GTP-Binding Proteins; D019061:src-Family Kinases; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins