H-Ras signals to cytoskeletal machinery in induction of integrin-mediated adhesion of T cells.
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.
Tanaka
Y
Y
First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu, Japan. Tanaka@med.uoeh-u.ac.jp
Minami
Y
Y
Mine
S
S
Hirano
H
H
Hu
C D
CD
Fujimoto
H
H
Fujii
K
K
Saito
K
K
Tsukada
J
J
van Kooyk
Y
Y
Figdor
C G
CG
Kataoka
T
T
Eto
S
S
D000199:Actins / Q000378:metabolism; D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D001172:Arthritis, Rheumatoid; D002448:Cell Adhesion / Q000502:physiology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003285:Contractile Proteins; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015458:Leukemia, T-Cell; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051304:Profilins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D000077191:Wortmannin
D000199:Actins; D000730:Androstadienes; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003285:Contractile Proteins; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D019402:Macrophage Inflammatory Proteins; D008840:Microfilament Proteins; C495738:PFN1 protein, human; D051304:Profilins; D018799:Intercellular Adhesion Molecule-1; D003571:Cytochalasin B; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D000077191:Wortmannin