title: The tight junction protein ZO-2 and Janus kinase 1 mediate intercellular communications in vascular smooth muscle cells.
abstract: Recent evidence points to a multifunctional role of ZO-2, the tight junction protein of the MAGUK (membrane-associated guanylate kinase-like) family. Though ZO-2 has been found in cell types lacking tight junction structures, such as vascular smooth muscle cells (VSMC), little is known about ZO-2 function in these cells. We provide evidence that ZO-2 mediates specific homotypic cell-to-cell contacts between VSMC. Using mass spectrometry we found that ZO-2 is associated with the non-receptor tyrosine kinase Jak1. By generating specific ZO-2 constructs we further found that the N-terminal fragment of ZO-2 molecule is responsible for this interaction. Adenovirus-based expression of Jak1 inactive mutant demonstrated that Jak1 mediates ZO-2 tyrosine phosphorylation. By means of RNA silencing, expression of Jak1 mutant form and fluorescently labeled ZO-2 fusion protein we further specified that active Jak1, but not Jak1 inactive mutant, mediates ZO-2 localization to the sites of intercellular contacts. We identified the urokinase receptor uPAR as a pre-requisite for these cellular events. Functional requirement of the revealed signaling complex for VSMC network formation was confirmed in experiments using Matrigel and in contraction assay. Our findings imply involvement of the ZO-2 tight junction independent signaling complex containing Jak1 and uPAR in VSMC intercellular communications. This mechanism may contribute to vascular remodeling in occlusive cardiovascular diseases and in arteriogenesis.
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tkachuk
authors.forename: Sergey
authors.initials: S
authors.lastname: Tkachuk
authors.forename: Margret
authors.initials: M
authors.lastname: Patecki
authors.forename: Angelika
authors.initials: A
authors.lastname: Kusch
authors.forename: Elena
authors.initials: E
authors.lastname: Korenbaum
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Inna
authors.initials: I
authors.lastname: Dumler
mesh_terms: D002450:Cell Communication; D002478:Cells, Cultured; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D010766:Phosphorylation; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000502:physiology*; D062827:Zonula Occludens-2 Protein
chemical_list: D008565:Membrane Proteins; D055293:Receptors, Urokinase Plasminogen Activator; C569046:TJP2 protein, human; D062827:Zonula Occludens-2 Protein; D053613:Janus Kinase 1