Adherens junctions and tight junctions are regulated via different pathways by progastrin in epithelial cells
2003
Adhesion between neighbouring epithelial cells is a crucial and tightly
controlled process. In the gastrointestinal tract, the integrity of cell-cell
contacts is essential for the regulation of electrolyte absorption and for the
prevention of tumour metastasis. We recently showed that migration of the
gastric epithelial cell line IMGE-5 is stimulated by the nonamidated form of
the hormone gastrin 17 . Here, we examine the effect on cell-cell
adhesion of the prohormone progastrin, the concentration of which is increased
in the plasma of patients with colorectal carcinoma. Progastrin induced the dissociation of both tight junction (TJ) and
adherens junction (AJ) complexes in IMGE-5 cells. In progastrin-secreting
DLD-1 human colorectal carcinoma cells, expression of an antisense gastrin
construct restored membrane localisation of zonula occludens-1 (ZO-1),
occludin, β-catenin and E-cadherin. This restoration was reversed by
treatment with exogenous progastrin. Endogenous or exogenous progastrin also
increased the paracellular flux of mannitol, and induced cell migration of
several gastrointestinal cell lines. In addition, progastrin enhanced Src
tyrosine kinase activity and induced a spatial delocalisation of protein
kinase Cα. Using dominant-negative mutants and pharmacological
inhibitors, we showed that the stimulation of Src kinase activity was
essential for the regulation of TJs. By contrast, the dissociation of AJs
involved phosphatidylinositol 3-kinase, partly through the formation of a
complex with protein kinase Cα. We conclude that separate pathways
mediate the disruption of AJs and TJs by progastrin. Either pathway may
contribute to the co-carcinogenic role of this prohormone in colorectal
carcinoma.
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