Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK.
Transcriptional repression of E-cadherin, characteristic of epithelial to mesenchymal transition, is often found also during tumor cell invasion. At metastases, migratory fibroblasts sometimes revert to an epithelial phenotype, by a process involving regulation of the E-cadherin-beta-catenin complex. We investigated the molecular basis of this regulation, using human colon cancer cells with aberrantly activated beta-catenin signaling. Sparse cultures mimicked invasive tumor cells, displaying low levels of E-cadherin due to transcriptional repression of E-cadherin by Slug. Slug was induced by beta-catenin signaling and, independently, by ERK. Dense cultures resembled a differentiated epithelium with high levels of E-cadherin and beta-catenin in adherens junctions. In such cells, beta-catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable. Disruption of E-cadherin-mediated contacts resulted in nuclear localization and signaling by beta-catenin, induction of Slug and inhibition of E-cadherin transcription, without changes in ErbB-1/2 and ERK activation. This autoregulation of E-cadherin by cell-cell adhesion involving Slug, beta-catenin and ERK could be important in tumorigenesis.
Conacci-Sorrell
Maralice
M
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Simcha
Inbal
I
Ben-Yedidia
Tamar
T
Blechman
Janna
J
Savagner
Pierre
P
Ben-Ze'ev
Avri
A
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D020928:Mitogen-Activated Protein Kinases