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The GTPase Rap1 regulates phorbol 12-myristate 13-acetate-stimulated but not ligand-induced beta 1 integrin-dependent leukocyte adhesion.

The Journal of Biological Chemistry

physiology, Antigens, CD29, rap1 GTP-Binding Proteins, metabolism, Tyrosine, pharmacology, Tetradecanoylphorbol Acetate, Protein Kinase C, Phosphorylation, Nuclear Proteins, Ligands, cytology, Leukocytes, Jurkat Cells, Humans, GTPase-Activating Proteins, Fibronectins, Enzyme Activation, Cytochalasin D, Cell Adhesion

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      Abstract

      Leukocyte migration from bloodstream to tissue requires rapid, coordinated regulation of integrin-dependent adhesion and de-adhesion. In a previous study we demonstrated that inhibition of protein geranylgeranylation inhibited phorbol ester-stimulated avidity modulation of beta(1) integrin in several leukocyte cell lines. Both RhoA and Rap1 require post-translational modification by geranylgeranylation for full function. In this report we identify Rap1, not RhoA, as a critical geranylgeranylated protein mediating phorbol ester-stimulated beta(1) and beta(2) integrin-dependent adhesion of Jurkat cells. Overexpression of the Rap1-specific GTPase-activating protein, SPA-1, or inactivated form of Rap1 (N17Rap1) blocked phorbol ester-stimulated adhesion of Jurkat cells to fibronectin (alpha(4)beta(1)) and ICAM-1 (alpha(L)beta(2)). With high concentrations of fibronectin as ligand, Jurkat cells adhered spontaneously without phorbol ester stimulation. Unlike the phorbol ester-stimulated adhesion, adhesion induced by high density ligand was not dependent upon Rap1 activation or actin cytoskeleton reorganization. Thus, the "inside-out" adhesion signal induced by phorbol ester and the "outside-in" signal induced by high density ligand involve different pathways.

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      Journal
      10.1074/jbc.M206208200
      12091396

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