Intercellular Adhesion Deficiencies

Although loss of E-cadherin is well associated with a more aggressive cell phenotype, its expression is not altered in our TAM-R cells. However, consistent with the observed poor cell-cell adhesion and the increased invasiveness of these cells, TAM-R cells display evidence of dysfunction of components of the E-cadherin adhesion system since P-catenin, an element reported to interact with E-cadherin and the actin cytoskeleton, is considerably modified (4). Using integrated microarray and signalling studies we have revealed that P-catenin expression is increased at the mRNA/protein level whilst its phosphorylation status is significantly modified (elevated tyrosine phosphorylation, decreased serine/threonine phosphorylation). This deregulation is associated with PI3K/AKT-induced inactivation of GSK3R in TAM-R cells resulting in reduced association of P-catenin with E-cadherin. As a consequence, a disruption of cell-cell contacts and elevated migration and invasion is seen. Further evidence for an impaired adherens junction system has come from studies in which E-cadherin function has been neutralised using the calcium chelator, EGTA, or the HECD-1 antibody; these have only a modest impact on TAM-R invasion in marked contrast to the promotion of this feature in parental MCF-7 cells. Furthermore, failure of GSK3P/ubiquitin-mediated degradation of P-catenin in TAM-R cells results in elevated intracellular levels of P-catenin, promoting its nuclear translocation and interaction with the TCF/LEF-1 transcription factor. This triggers increased transcription of P-catenin/TCF/LEF-1 target genes, including CD44 which has, in turn, been linked to invasive cellular responses and EMT (4).

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