{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:47:55Z","timestamp":1790743675116,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2003,10,13]],"date-time":"2003-10-13T00:00:00Z","timestamp":1066003200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2004,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In vitro experiments have shown that the establishment of cell\u2013cell contacts in intestinal epithelial cell cultures is a critical step in initiating ERK inhibition, cell cycle arrest, and induction of the differentiation process. Herein, we determined the mechanisms through which E\u2010cadherin\u2010mediated cell\u2013cell contacts modulate the ERK pathway in intestinal epithelial cells. We report that: (1) removal of calcium from the culture medium of newly confluent Caco\u20102\/15 cells (30 min, 4 mM EGTA) results in the disruption of both adherens and tight junctions and clearly decreases Akt phosphorylation while increasing MEK and ERK activities. Akt, MEK, and ERK activation levels return to control levels 60 min after calcium restoration; (2) the use of E\u2010cadherin blocking antibodies efficiently prevents Akt phosphorylation and MEK\u2013ERK inhibition after 70 min of calcium restoration; (3) using the PI3K inhibitor LY294002 (15 \u03bcM) in calcium switch experiments, we demonstrate that the assembly of adherens junctions activates Akt activity and triggers the inhibition of ERK1\/2 activities in a PI3K\u2010dependent manner; (4) adenoviral infection of confluent Caco\u20102\/15 cells with a constitutively active mutant of Akt1 strongly represses ERK1\/2 activities; (5) inhibition of PI3K abolishes Akt activity but leads to a rapid and sustained activation of the MEK\u2013ERK1\/2 in confluent differentiating Caco\u20102\/15 cells, but not in undifferentiated growing Caco\u20102\/15 cells. Our data suggest that E\u2010cadherin engagement leads to MEK\/ERK inhibition in a PI3K\/Akt\u2010dependent pathway. This mechanism may account for the role of E\u2010cadherin in proliferation\/differentiation transition along the crypt\u2010villus axis of the human intestinal epithelium. J. Cell. Physiol. 199: 32\u201339, 2004\u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.10432","type":"journal-article","created":{"date-parts":[[2004,2,18]],"date-time":"2004-02-18T10:00:30Z","timestamp":1077098430000},"page":"32-39","source":"Crossref","is-referenced-by-count":82,"title":["Down\u2010regulation of MEK\/ERK signaling by E\u2010cadherin\u2010dependent PI3K\/Akt pathway in differentiating intestinal epithelial 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