title: Cortactin is a scaffolding platform for the E-cadherin adhesion complex and is regulated by protein kinase D1 phosphorylation.
abstract: Dynamic regulation of cell-cell adhesion by the coordinated formation and dissolution of E-cadherin-based adherens junctions is crucial for tissue homeostasis. The actin-binding protein cortactin interacts with E-cadherin and enables F-actin accumulation at adherens junctions. Here, we were interested to study the broader functional interactions of cortactin in adhesion complexes. In line with literature, we demonstrate that cortactin binds to E-cadherin, and that a posttranslational modification of cortactin, RhoA-induced phosphorylation by protein kinase D1 (PKD1; also known as PRKD1) at S298, impairs adherens junction assembly and supports their dissolution. Two new S298-phosphorylation-dependent interactions were also identified, namely, that phosphorylation of cortactin decreases its interaction with β-catenin and the actin-binding protein vinculin. In addition, binding of vinculin to β-catenin, as well as linkage of vinculin to F-actin, are also significantly compromised upon phosphorylation of cortactin. Accordingly, we found that regulation of cell-cell adhesion by phosphorylation of cortactin downstream of RhoA and PKD1 is vitally dependent on vinculin-mediated protein interactions. Thus, cortactin, unexpectedly, is an important integration node for the dynamic regulation of protein complexes during breakdown and formation of adherens junctions.
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Sroka
authors.affiliation: Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N1 - Herestraat 49 bus 901, Leuven 3000, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Van Lint
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Sarah-Fee
authors.initials: SF
authors.lastname: Katz
authors.affiliation: Department for Animal Breeding and Biotechnology, LMU Munich, Gene Center, Feodor-Lynen-Str. 25, Munich 81377, Germany.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleger
authors.affiliation: Department of Visceral Surgery, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Paschke
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm 89081, Germany tim.eiseler@uniklinik-ulm.de.
authors.forename: Tim
authors.identifier: 0000-0001-7819-4659
authors.initials: T
authors.lastname: Eiseler
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D003106:Colon / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D050396:TRPP Cation Channels / Q000378:metabolism*; D016596:Vinculin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051356:Cortactin; D010768:Phosphoserine; D050396:TRPP Cation Channels; D016596:Vinculin; C513384:CDH1 protein, human
keywords: Adherens junction; CDH1; Cadherin-1; Cortactin; E-cadherin; Epithelial cadherin; PKD; Protein kinase D; Vinculin