title: Opposing roles of integrin alpha6Abeta1 and dystroglycan in laminin-mediated extracellular signal-regulated kinase activation.
abstract: Laminin-integrin interactions can in some settings activate the extracellular signal-regulated kinases (ERKs) but the control mechanisms are poorly understood. Herein, we studied ERK activation in response to two laminins isoforms (-1 and -10/11) in two epithelial cell lines. Both cell lines expressed beta1-containing integrins and dystroglycan but lacked integrin alpha6beta4. Antibody perturbation assays showed that both cell lines bound to laminin-10/11 via the alpha3beta1and alpha6beta1 integrins. Although laminin-10/11 was a stronger adhesion complex than laminin-1 for both cell lines, both laminins activated ERK in only one of the two cell lines. The ERK activation was mediated by integrin alpha6beta1 and not by alpha3beta1 or dystroglycan. Instead, we found that dystroglycan-binding domains of both laminin-1 and -10/11 suppressed integrin alpha6beta1-mediated ERK activation. Moreover, the responding cell line expressed the two integrin alpha6 splice variants, alpha6A and alpha6B, whereas the nonresponding cell line expressed only alpha6B. Furthermore, ERK activation was seen in cells transfected with the integrin alpha6A subunit, but not in alpha6B-transfected cells. We conclude that laminin-1 and -10/11 share the ability to induce ERK activation, that this is regulated by integrin alpha6Abeta1, and suggest a novel role for dystroglycan-binding laminin domains as suppressors of this activation.
authors.affiliation: Department of Cell and Molecular Biology, Lund University, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Ferletta
authors.forename: Yamato
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Jan F
authors.initials: JF
authors.lastname: Talts
authors.forename: Madeleine
authors.initials: M
authors.lastname: Durbeej
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
authors.forename: Rupert
authors.initials: R
authors.lastname: Timpl
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Peter
authors.initials: P
authors.lastname: Ekblom
authors.forename: Elke
authors.initials: E
authors.lastname: Genersch
mesh_terms: D003598:Cytoskeletal Proteins / Q000378:metabolism*; D049030:Dystroglycans; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D016023:Integrins; D007797:Laminin; D008024:Ligands; D008562:Membrane Glycoproteins; C119013:laminin 10; C474559:laminin 11 protein, human; D049030:Dystroglycans; D020928:Mitogen-Activated Protein Kinases