title: Alpha4beta1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the alpha4-cytoplasmic domain.
abstract: The capacity of integrins to mediate adhesiveness is modulated by their cytoplasmic associations. In this study, we describe a novel mechanism by which alpha4-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the alpha4 tail that disrupts paxillin binding, alpha4(Y991A), reduced talin association to the alpha4beta1 heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed alpha4beta1-dependent capture and adhesion strengthening of Jurkat T cells to VCAM-1 under shear stress. The mutant retained intrinsic avidity to soluble or bead-immobilized VCAM-1, supported normal cell spreading at short-lived contacts, had normal alpha4-microvillar distribution, and responded to inside-out signals. This is the first demonstration that cytoskeletal anchorage of an integrin enhances the mechanical stability of its adhesive bonds under strain and, thereby, promotes its ability to mediate leukocyte adhesion under physiological shear stress conditions.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. ronen.alon@weizmann.ac.il
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
authors.forename: Sara W
authors.initials: SW
authors.lastname: Feigelson
authors.forename: Eugenia
authors.initials: E
authors.lastname: Manevich
authors.forename: David M
authors.initials: DM
authors.lastname: Rose
authors.forename: Julia
authors.initials: J
authors.lastname: Schmitz
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Overby
authors.forename: Eitan
authors.initials: E
authors.lastname: Winter
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Vera
authors.initials: V
authors.lastname: Shinder
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Matthews
authors.forename: Maya
authors.initials: M
authors.lastname: Sokolovsky-Eisenberg
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: Martin
authors.initials: M
authors.lastname: Benoit
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D039441:Integrin alpha4 / Q000378:metabolism* / Q000494:pharmacology; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D019169:Jurkat Cells; D008024:Ligands; D009088:Mucoproteins / Q000378:metabolism; D009154:Mutation; D051419:Paxillin / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D016608:Talin; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D008024:Ligands; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D051419:Paxillin; D011994:Recombinant Proteins; C436513:TLN2 protein, human; D016608:Talin; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4