title: Hippo pathway elements Co-localize with Occludin: A possible sensor system in pancreatic epithelial cells.
abstract: External adherens junction-based cell-cell contacts involving E-cadherin interactions function to sense planar cell status and modulate epithelial cell proliferation through Hippo (Hpo) and non-canonical Wnt pathways signaling. We hypothesized these regulatory processes should also be sensitive to a similar cell-cell contact sensor associated with apical-basal polarity events at epithelial surfaces. We used 2 human pancreatic cancer cell lines to explore this hypothesis: one with the capacity to form functional tight junction structures and polarize (HPAFII) and one lacking this capacity (AsPc1). Occludin (Ocln), a tetraspanning protein associated with TJ structures and capable of establishing external cell-cell contacts, was observed to partially co-localize with Hpo elements YAP (c-yes associated protein) and TEAD (TEA-dependent), which function to drive a proliferative transcription program. Treatment with dobutamine, known to affect YAP, was shown to suppress proliferation in an Ocln-dependent manner. Blockade of protein kinase C-zeta (PKC-ζ) diminished transepithelial electrical resistance (TER) of HPAFII monolayers that was not corrected by dobutamine treatment while the loss of TER resulting from inhibition of ROCK1 could be partially recovered. Examination of normal and cancerous human pancreatic biopsies showed that the cellular localization of Ocln, c-Yes, YAP, and TEAD were similar to HPAFII for normal cells and AsPc1 for cancerous cells. Together, these results suggest a link between Hpo and signals emanating from cell-cell contacts involving Ocln that may regulate pancreatic cell proliferation through the coordination of planar cell polarity with apical-basal polarity events.
authors.affiliation: Department of Pharmacy and Pharmacology; University of Bath ; Bath, UK.
authors.forename: Ana Santos
authors.initials: AS
authors.lastname: Cravo
authors.affiliation: Department of Pharmacy and Pharmacology; University of Bath ; Bath, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Carter
authors.affiliation: Department of Surgery; Koc University School of Medicine ; Istanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Department of Pharmacy and Pharmacology; University of Bath ; Bath, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Harvey
authors.affiliation: Department of Biology and Biochemistry; University of Bath ; Bath, UK.
authors.forename: Makoto
authors.initials: M
authors.lastname: Furutani-Seiki
authors.affiliation: Department of Pharmacy and Pharmacology; University of Bath ; Bath, UK.
authors.forename: Randall
authors.initials: R
authors.lastname: Mrsny
keywords: YAP; dobutamine; occludin; pancreatic cancer cells; tight junctions