title: The small GTP-binding proteins Rho and Rac induce T cell adhesion to the mucosal addressin MAdCAM-1 in a hierarchical fashion.
abstract: Here we report that an activator (AIF4-) of heterotrimeric GTP-binding proteins (G-proteins) and inhibitors (lovastatin and C3 exoenzyme) of small GTP-binding proteins regulate the induction of alpha4beta7-mediated adhesion of TK-1 T lymphoma cells (alpha4+beta7+beta1-) to the mucosal addressin cell adhesion molecule MAdCAM-1. Activation of cell adhesion by AIF4- was abrogated by lovastatin, thereby establishing a link between heterotrimeric G-proteins and small GTP-binding proteins in the regulation of alpha4beta7-mediated cell adhesion. Increased numbers of cells bound MAdCAM-1-coated microspheres following activation with AIF4-, discounting an obligatory role for cell spreading in alpha4beta7-mediated cell adhesion. MAdCAM-1-Fc dimers triggered ligand-induced clustering of alpha4beta7 in response to AIF4- and Mn2+-induced activation of integrins. Hence alpha4beta7 cluster formation may be responsible, at least in part, for inducing cell adhesion in response to both extracellular and intracellular signals that impact on integrin function. Electroporation of constitutively active V14RhoA and V12Rac1 recombinant proteins into TK-1 cells revealed that both RhoA and Rac1 induce alpha4beta7 adhesion to MAdCAM-1. Activation is hierarchical since Rac1 is unable to directly activate alpha4beta7, but induces cell adhesion via RhoA, whereas the transient induction of cell adhesion mediated by RhoA is dependent on the activities of protein tyrosine kinases and protein kinase(s) C.
authors.affiliation: Department of Molecular Medicine, School of Medicine and Health Science, University of Auckland, Auckland, New Zealand.
authors.forename: W V
authors.initials: WV
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: R W
authors.initials: RW
authors.lastname: Berg
authors.forename: E
authors.initials: E
authors.lastname: Leung
authors.forename: G W
authors.initials: GW
authors.lastname: Krissansen
mesh_terms: D016475:3T3 Cells; D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules; D003176:Complement C3 / Q000502:physiology; D018274:Electroporation; D005459:Fluorides / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D007136:Immunoglobulins / Q000276:immunology*; D016023:Integrins / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D016399:Lymphoma, T-Cell; D051379:Mice; D009088:Mucoproteins / Q000276:immunology*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D017607:Aluminum Compounds; D015815:Cell Adhesion Molecules; D003176:Complement C3; D007136:Immunoglobulins; D016023:Integrins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; C071777:integrin alpha4beta7; C050992:tetrafluoroaluminate; C016658:phorbolol myristate acetate; D019833:Genistein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D005459:Fluorides