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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3496-3497. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stork, P. J. S. Search for Related Content PubMed Articles by Stork, P. J. S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Ghandour et al, page 3682 Rap1: selective activator of ß2 integrins? Philip J. S. Stork VOLLUM INSTITUTE In T cells, Rap1 is well-recognized as a major mediator of inside-out signaling to integrins following stimulation by antigen and chemokines. Ghandour and colleagues have identified a selective role for Rap1 in human T cells in chemokine-dependent adhesion via LFA-1, but not VLA-4. Their study highlights the specificity of Rap1 for LFA-1 in SDF-1–mediated adhesion, and shows that PLC and the Rap1 exchanger CalDAG-GEFI are required. Two major types of integrins are highly expressed in T lymphocytes: lymphocyte-function–associated antigen-1 (LFA-1, or Lß2) and the very late antigens (including VLA-4 or 4ß1). LFA-1 binds intracellular adhesion molecules (ICAM-1, -2, or -3), and VLAs bind to both vascular cell-adhesion molecule-1 (VCAM-1) and fibronectin to regulate T-cell/antigen recognition, extravasation, and homing to target organs. These interactions are enhanced by a variety of stimuli that increase both affinity and avidity of the integrins for their ligands in a process termed "inside-out signaling."1 One intracellular small G protein, Rap1, a member of the Ras superfamily, is activated by these diverse stimuli and is thought to couple these signals to integrin activation.2 Other signaling proteins have been implicated as well, including phospholipase C (PLC), phosphoinositol-3 kinase (PI3-K), protein kinase C (PKC), and intracellular second messengers calcium and diacylglycerol (DAG). Recent research has focused on determining how these diverse signaling pathways converge on Rap1, and whether the mode of Rap1 activation dictates the selectivity of Rap1's actions for specific integrins. Ghandour and colleagues have begun to answer these questions by examining the specific integrins activated by the chemokine stromal cell-derived factor 1 (SDF-1, also called CXCL12). In human T cells, SDF-1 activates adhesion to ICAM via LFA-1 and to VCAM via VLA-4. Surprisingly, Rap1 was required only for SDF-1's enhancement of adhesion to ICAM, a finding that was mimicked by the phorbol ester PMA, a potent agonist of PKC. However, PKC inhibition blocked only adhesion through VLA-4. Taken together, these data demonstrate that Rap1 can be activated in a PKC-independent manner to activate LFA-1, and that PKC can act independently of Rap1 to stimulate VLA-4. In contrast, other studies that show a requirement for Rap1 in chemokine- and VLA-4 – dependent adhesion have utilized murine lymphocytes3,4 and human Jurkat cells.5 It will be important to further characterize these species differences. Interestingly, in this study, adhesion through both LFA-1 and VLA-4 required PLC. The Rap1 exchanger CalDAG-GEF1 is activated by direct binding of calcium and DAG, making it highly responsive to PLC.6 Using a knockdown approach, the authors show that CalDAG-GEF1 is required for the LFA-1–dependent effects of both SDF-1 and PMA (see figure). The study identifies key questions for future research. How does PLC/PKC activation by chemokines activate VLA-4 independently of Rap1? Are the small G proteins Rac and Rho involved, as suggested by others?7 Is there a Rap1-independent role for PKD1, a kinase that is activated by PKC and associates with ß1 integrins?5 How is the pool of Rap1 activated by SDF-1 restricted to the activation of LFA-1? Do specific adaptor proteins, including adhesion- and degranulation-promoting adaptor protein (ADAP) and Src kinase-associated phosphoprotein of 55kDa (SKAP-55), or the selective recruitment of Rap1 effectors RapL and/or RAIM, contribute to this specificity?8 View larger version (33K): [in this window] [in a new window]   Model for integrin activation by the chemokine SDF-1 in human T cells. SDF-1 binding to the G protein–coupled receptor CXCR4 activates Gq-coupled signaling to PLC-, generating DAG and releasing intracellular calcium via IP3. These intracellular second messengers activate PKC and CalDAG-GEF1 to initiate inside-out signaling to the integrins VLA-4 (4ß1) and LFA-1 (Lß2), respectively. The mechanism by which PKC triggers VLA-4 binding to VCAM is unknown. CalDAG-GEF1 is a Rap1-specific guanine nucleotide exchange factor whose catalytic (GEF) domain is activated by direct binding of calcium and DAG to adjacent EF hand domains and a DAG-binding motif. Rap1 activation by CalDAG-GEF1 selectively activates LFA-1 binding to ICAM. This may require the actions of the Rap1 effectors RIAM and RapL. RapL binds to LFA-1 and may help bring Rap1 to the plasma membrane. Adaptor molecules ADAP and SKAP-55 may also facilitate coupling of Rap1 to LFA-1.   Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Shattil SJ and Newman PJ. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 2004; 104:1606–1615.[Abstract/Free Full Text] Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol 2001; 2:369–377.[CrossRef][Medline] [Order article via Infotrieve] Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele JS, Zwartkruis FJ. Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Mol Cell Biol 2006; 26:643–653.[Abstract/Free Full Text] Shimonaka M, Katagiri K, Nakayama T, et al. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J Cell Biol 2003; 161:417–427.[Abstract/Free Full Text] Medeiros RB, Dickey DM, Chung H, et al. Protein kinase D1 and the beta1 integrin cytoplasmic domain control beta1 integrin function via regulation of Rap1 activation. Immunity 2005; 23:213–226.[CrossRef][Medline] [Order article via Infotrieve] Crittenden JR, Bergmeier W, Zhang Y, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med 2004; 10:982–986.[CrossRef][Medline] [Order article via Infotrieve] Garcia-Bernal D, Wright N, Sotillo-Mallo E, et al. Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1. Mol Biol Cell 2005; 16:3223–3235.[Abstract/Free Full Text] Menasche G, Kliche S, Bezman N, Schraven B. Regulation of T-cell antigen receptor-mediated inside-out signaling by cytosolic adapter proteins and Rap1 effector molecules. Immunol Rev 2007; 218:82–91.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin–mediated human T-cell adhesion Haifa Ghandour, Xavier Cullere, Angeles Alvarez, Francis W. Luscinskas, and Tanya N. Mayadas Blood 2007 110: 3682-3690. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stork, P. J. S. 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