Katagiri, K., Maeda, A., Shimonaka, M. & Kinashi, T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat. Immunol. 4, 741−748

Department of Molecular Immunology and Allergy, Graduate School of Medicine, Kyoto University, Yoshida-konoe, Sakyo-ku, Kyoto 606-8501 Japan.
Nature Immunology (Impact Factor: 20). 09/2003; 4(8):741-8. DOI: 10.1038/ni950
Source: PubMed


The small GTPase Rap1 is a potent activator of leukocyte integrin. However, the regulatory mechanism involved is unknown. Here, we identify the Rap1 effector, RAPL, as an essential regulator in this activation. RAPL was enriched in mouse lymphoid tissues and associated with Rap1 after stimulation by the T cell receptor and with chemokine CXCL12. Human RAPL stimulated lymphocyte polarization and the patch-like redistribution of lymphocyte-function-associated antigen 1 (LFA-1) to the leading edge, resulting in enhanced adhesion to intercellular adhesion molecule 1 (ICAM-1). Triggered by activated Rap1, RAPL associated with LFA-1 and rapidly relocated to the leading edge and accumulated at immunological synapses. Thus, RAPL regulates lymphocyte adhesion through the spatial distribution of LFA-1.

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    • "38 Crk, through its association with C3G and subsequent control of Rap1, likely has a role in the regulation of LFA-1 activation and subsequent target cell adhesion.38, 39, 40, 41, 42 Interestingly, inhibitory receptors also serve to ‘license' NK cells during their developmental process, and NK cells that lack the recognition of MHC molecules during maturation are rendered hyporesponsive, at least partially by reduced signaling from activating receptors to LFA-1. Unlicensed cells form fewer conjugates, but those that do conjugate mediate lytic granule polarization normally.43 "
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    ABSTRACT: Natural killer (NK) cell-mediated cytotoxicity is governed by the formation of a lytic immune synapse in discrete regulated steps, which give rise to an extensive array of cellular checkpoints in accessing NK cell-mediated cytolytic defense. Appropriate progression through these cell biological steps is critical for the directed secretion of specialized secretory lysosomes and subsequent target cell death. Here we highlight recent discoveries in the formation of the NK cell cytolytic synapse as well as the molecular steps and cell biological checkpoints required for this essential host defense process.Immunology and Cell Biology advance online publication, 21 January 2014; doi:10.1038/icb.2013.96.
    Full-text · Article · Jan 2014 · Immunology and Cell Biology
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    • "In sharp contrast, activation of b2-integrins needs to be fully switchable from inactive to active within seconds to allow extravasation of blood-borne leukocytes. In addition, many of the integrin activators are specific for b2-integrins over b1-integrins (e.g., the guanosine triphosphatase Rap1 regulating LFA-1 vesicle traffic, RAPL regulating LFA-1 transport, and adaptor 14-3-3 binding to phosphorylated b2-integrin), and the Rap1-RAPL-dependent LFA-1 activation involves binding to the alpha-subunit cytoplasmic region of LFA-1 immediately adjacent to the SHARPIN-binding site (Hogg et al., 2011; Katagiri et al., 2003). This suggests that SHARPIN-mediated LFA-1 inactivation may Cell Reports 5, 619–628, November 14, 2013 ª2013 The Authors 625 Figure 4. Sharpin Deactivates LFA-1, Improves Lymphocyte Extravasation, and Re-expression of SHARPIN Rescues the Uropod and Migration Defects of SHARPIN-Deficient Cells (A and B) Adhesion (A) and migration (B) of human PBMC transfected with SHARPIN siRNA or control siRNA on recombinant human ICAM-1 and the efficacy of knockdown on SHARPIN protein levels. "
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    ABSTRACT: SHARPIN-deficient mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of SHARPIN in lymphocyte adhesion, polarization, and migration. We found that SHARPIN localizes to the trailing edges (uropods) of both mouse and human chemokine-activated lymphocytes migrating on intercellular adhesion molecule-1 (ICAM-1), which is one of the major endothelial ligands for migrating leukocytes. SHARPIN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHARPIN-deficient lymphocytes decreases the migration velocity. The adhesion, migration, and uropod defects in SHARPIN-deficient lymphocytes were rescued by reintroducing SHARPIN into the cells. Mechanistically, we show that SHARPIN interacts directly with lymphocyte-function-associated antigen-1 (LFA-1), a leukocyte counterreceptor for ICAM-1, and inhibits the expression of intermediate and high-affinity forms of LFA-1. Thus, SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells.
    Full-text · Article · Nov 2013 · Cell Reports
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    • "Our results show a novel role of Mst1 in the process of IS formation by natural Treg cells. We previously showed that Mst1 and RAPL were localized in vesicle compartments and relocated to the T-APC contact sites with co-localization with LFA-1 [20,32]. The current study extends the previous studies and indicate that a linkage of spatial organization of LFA-1/ICAM-1 and TCR/pMHC bindings. "
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    ABSTRACT: Although the cell-to-cell contact between CD4(+)Foxp3(+) regulatory T (Treg) and their target cells is important for the suppressor function of Treg cells, the regulation of this process is not well understood. Here we show that the Mst1 kinase plays a critical role in the suppressor function of Treg cells through regulation of cell contact dependent processes. Mst1 (-/-) Treg cells failed to prevent the development of experimental colitis and antigen-specific suppression of naïve T cells proliferation in vitro. Mst1 (-/-) Treg cells exhibited defective interactions with antigen-presenting dendritic cells (DCs), resulting in reduced down-regulation of costimulatory molecules. While wild-type CD4(+) Foxp3(+) Treg cells formed mobile immunological synapses on supported planar membrane, Mst1 (-/-) Treg cells did not exhibit ICAM-1 ring or central peptide-MHC clustering. Using two-photon imaging we showed that antigen-specific wild-type Treg cells exhibited dynamic mobile contacts with antigen-pulsed DCs bearing stably associated naïve T cells. In contrast, Mst1 (-/-) Treg had impairments in their interactions with DCs. Thus, Mst1 is required for Treg cells to mediate contact-dependent suppressor functions.
    Full-text · Article · Sep 2013 · PLoS ONE
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