H-Ras signals to cytoskeletal machinery in induction of integrin-mediated adhesion of T cells

Y Tanaka, Y Minami, S Mine, H Hirano, C D Hu, H Fujimoto, K Fujii, K Saito, J Tsukada, Y van Kooyk, C G Figdor, T Kataoka, S Eto

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The adhesive function of integrins is regulated through cytoplasmic signaling. The present study was performed to investigate the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemokines. Adhesion of T cells induced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta was inhibited by pertussis toxin, wortmannin, and cytochalasin B, suggesting that both G protein-sensitive phosphatidylinositol (PI) 3-kinase activation and cytoskeletal assemblies are involved. The chemokine-induced T cell adhesion could be mimicked by expression of small G proteins, fully activated H-RasV12, or H-RasV12Y40C mutant, which selectively binds to PI 3-kinase, in T cells, inducing activated form of LFA-1alpha and LFA-1-dependent adhesion to ICAM-1. H-Ras expression also induced F-actin polymerization which colocalized with profilin in T cells. Adult T cell leukemia (ATL) cells spontaneously adhered to ICAM-1, which depended on endogenous MIP-1alpha and MIP-1beta through activation of G protein-sensitive PI 3-kinase. H-Ras signal pathway, leading to PI 3-kinase activation, also induced active configuration of LFA-1 and LFA-1-mediated adhesion of ATL cells, whereas expression of a dominant-negative H-Ras mutant failed to do. Profilin-dependent spontaneous polymerization of F-actin in ATL cells was reduced by PI 3-kinase inhibitors. In this paper we propose that H-Ras-mediated activation of PI 3-kinase can be involved in induction of LFA-1-dependent adhesion of T cells, which is relevant to chemokine-mediated signaling, and that profilin may form an important link between chemokine- and/or H-Ras-mediated signals and F-actin polymerization, which results in triggering of LFA-1 on T cells or leukemic T cells.

Original languageEnglish
Pages (from-to)6209-16
Number of pages8
JournalJournal of Immunology
Issue number11
Publication statusPublished - 1 Dec 1999


  • Actins/metabolism
  • Adult
  • Androstadienes/pharmacology
  • Arthritis, Rheumatoid
  • Cell Adhesion/physiology
  • Chemokine CCL3
  • Chemokine CCL4
  • Contractile Proteins
  • Cytochalasin B/pharmacology
  • Cytoskeleton/physiology
  • Endothelium, Vascular/cytology
  • GTP-Binding Proteins/metabolism
  • Genes, ras/physiology
  • Humans
  • Integrins/metabolism
  • Intercellular Adhesion Molecule-1/metabolism
  • Leukemia, T-Cell
  • Lymphocyte Function-Associated Antigen-1/metabolism
  • Macrophage Inflammatory Proteins/metabolism
  • Microfilament Proteins/metabolism
  • Phosphatidylinositol 3-Kinases/metabolism
  • Profilins
  • Signal Transduction
  • T-Lymphocytes/physiology

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