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Membrane-Proximal Signaling Events in Beta-2 Integrin Activation

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Cell Communication in Nervous and Immune System

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 43))

Abstract

In the immune system, integrins have essential roles in leukocyte trafficking and function. These include immune cell attachment to endothelial and antigen-presenting cells, cytotoxicity, and extravasation into tissues. The integrin leukocyte function-associated antigen-1 (LFA-1), which is exclusively expressed on hematopoietic cells, has been intensely studied since this receptor is important for many functions of the immune system. LFA-1 is involved in a) the interaction between T-cells and antigen presenting cells, b) the adhesion of cells to post-capillary high endothelial venules or to activated endothelium at sites of inflammation (extravasation), c) the control of cell differentiation and proliferation, and d) the regulation of T-cell effector functions. Therefore, a precise understanding of the spatial and temporal control of LFA-1 interaction with its cellular counter-receptors, the intercellular adhesion molecules (ICAM) -1, -2 and -3, in the various contexts, is of high interest. LFA-1 mediated adhesion is induced by several extracellular stimuli in different cell types. In T-cells, LFA-1 becomes activated upon signaling from the T-cell receptor (TCR), and upon cytokine and chemokine sensing. Adhesion of monocytes to ICAM-1 is induced by lipopolysaccharide (LPS), a component of the bacterial cell wall. To investigate the regulation of LFA-1 adhesiveness, research has focused on the identification of interaction partners of the intracellular portions of the integrin alpha and beta subunits. This review will highlight recent developments on transmembrane and intracellular signaling proteins, which have been implicated in beta-2 integrin activation.

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References

  1. Boehm T, Hofer S, Winklehner P, Kellersch B, Geiger C, Trockenbacher A, Neyer S, Fiegl H, Ebner S, Ivarsson L, Schneider R, Kremmer E, Heufler C, Kolanus W (2003) Attenuation of cell adhesion in lymphocytes is regulated by CYTIP, a protein which mediates signal complex sequestration. EMBO J 22:1014–1024

    Article  PubMed  CAS  Google Scholar 

  2. Bos JL (2005) Linking Rap to cell adhesion. Curr Opin Cell Biol 17:123–128

    Article  PubMed  CAS  Google Scholar 

  3. Calderwood DA (2004) Integrin activation. J Cell Sci 117:657–666

    Article  PubMed  CAS  Google Scholar 

  4. Calderwood DA, Ginsberg MH (2003) Talin forges the links between integrins and actin. Nat Cell Biol 8:694–697

    Article  CAS  Google Scholar 

  5. Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH (1999) The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J Biol Chem 274:28071–28074

    Article  PubMed  CAS  Google Scholar 

  6. Chardin P, Paris S, Antonny B, Robineau S, Beraud-Dufour S, Jackson CL, Chabre M (1996) A human exchange factor for ARF contains Sec7- and pleckstrin-homology domains. Nature 384:481–484

    Article  PubMed  CAS  Google Scholar 

  7. Caumont AS, Vitale N, Gensse M, Galas MC, Casanova JE, Bader MF (2000) Identification of a plasma membrane-associated guanine nucleotide exchange factor for ARF6 in chromaffin cells. Possible role in the regulated exocytotic pathway. J Biol Chem 275:15637–15644

    Article  PubMed  CAS  Google Scholar 

  8. de Bruyn KM, Rangarajan S, Reedquist KA, Figdor CG, Bos JL (2002) The small GTPase Rap1 is required for Mn(2+)- and antibody-induced LFA-1- and VLA-4-mediated cell adhesion. J Biol Chem 277:29468–29476

    Article  PubMed  CAS  Google Scholar 

  9. Derrien V, Couillault C, Franco M, Martineau S, Montcourrier P, Houlgatte R, Chavrier P (2002) A conserved C-terminal domain of EFA6-family ARF6-guanine nucleotide exchange factors induces lengthening of microvilli-like membrane protrusions. J Cell Sci 115:2867–2879

    PubMed  CAS  Google Scholar 

  10. Dierks H, Kolanus J, Kolanus W (2001) Actin cytoskeletal association of cytohesin-1 is regulated by specific phosphorylation of its carboxyl-terminal polybasic domain. J Biol Chem 276:37472–37481

    Article  PubMed  CAS  Google Scholar 

  11. Donaldson JG, Jackson CL (2000) Regulators and effectors of the ARF GTPases. Curr Opin Cell Biol 12:475–482

    Article  PubMed  CAS  Google Scholar 

  12. Geiger C, Nagel W, Boehm T, Van Kooyk Y, Figdor CG, Kremmer E, Hogg N, Zeitlmann L, Dierks H, Weber KS, Kolanus W (2000) Cytohesin-1 regulates beta-2 integrin-mediated adhesion through both ARF-GEF function and interaction with LFA-1. EMBO J 19:2525–2536

    Article  PubMed  CAS  Google Scholar 

  13. Jackson TR, Brown FD, Nie Z, Miura K, Foroni L, Sun J, Hsu VW, Donaldson JG, Randazzo PA (2000a) ACAPs are Arf6 GTPase-activating proteins that function in the cell periphery. J Cell Biol 151:627–638

    Article  PubMed  CAS  Google Scholar 

  14. Jackson TR, Kearns BG, Theibert AB (2000b) Cytohesins and centaurins: mediators of PI 3-kinase-regulated Arf signaling. Trends Biochem Sci 25:489–495

    Article  PubMed  CAS  Google Scholar 

  15. Franco M, Peters PJ, Boretto J, Van Donselaar E, Neri A, D'souza-Schorey C, Chavrier P (1999) EFA6, a sec7 domain-containing exchange factor for ARF6, coordinates membrane recycling and actin cytoskeleton organization. EMBO J 18:1480–1491

    Article  PubMed  CAS  Google Scholar 

  16. Frank S, Upender S, Hansen SH, Casanova JE (1998a) ARNO is a guanine nucleotide exchange factor for ADP-ribosylation factor 6. J Biol Chem 273:23–27

    Article  PubMed  CAS  Google Scholar 

  17. Frank S, Hatfield JC, Casanova JE (1998b) Remodeling of the actin cytoskeleton is coordinately regulated by protein kinase C and the ADP-ribosylation factor nucleotide exchange factor ARNO. Mol Biol Cell 9:3133–3146

    PubMed  CAS  Google Scholar 

  18. Griffiths EK, Krawczyk C, Kong YY, Raab M, Hyduk SJ, Bouchard D, Chan VS, Kozieradzki I, Oliveira-Dos-Santos AJ, Wakeham A, Ohashi PS, Cybulsky MI, Rudd CE, Penninger JM (2001) Positive regulation of T cell activation and integrin adhesion by the adapter Fyb/Slap. Science 293:2260–2263

    Article  PubMed  CAS  Google Scholar 

  19. Grotewiel MS, Beck CD, Wu KH, Zhu XR, Davis RL (1998) Integrin-mediated short-term memory in Drosophila. Nature 391:455–460

    Article  PubMed  CAS  Google Scholar 

  20. Hanada T, Lin L, Chandy KG, Oh SS, Chishti AH (1997) Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes. J Biol Chem 43:26899–26904

    Article  Google Scholar 

  21. Huang Y, Norton DD, Precht P, Martindale JL, Burkhardt JK, Wange RL (2005) Deficiency of ADAP/Fyb/SLAP-130 destabilizes SKAP55 in Jurkat T cells. J Biol Chem 280:23576–23583

    Article  PubMed  CAS  Google Scholar 

  22. Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25

    Article  PubMed  CAS  Google Scholar 

  23. Hynes RO (1999) Cell adhesion: old and new questions. Trends Cell Biol 9:M33–37

    Article  PubMed  CAS  Google Scholar 

  24. Katagiri K, Hattori M, Minato N, Irie S, Takatsu K, Kinashi T (2000) Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol Cell Biol 20:1956–1969

    Article  PubMed  CAS  Google Scholar 

  25. Inagaki T, Suzuki S, Miyamoto T, Takeda T, Yamashita K, Komatsu A, Yamauchi K, Hashizume K (2003) The retinoic acid-responsive proline-rich protein is identified in promyeloleukemic HL-60 cells. J Biol Chem 278:51685–51692

    Article  PubMed  CAS  Google Scholar 

  26. Katagiri K, Maeda A, Shimonaka M, Kinashi T (2003) RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol 4:741–748

    Article  PubMed  CAS  Google Scholar 

  27. Katagiri K, Shimonaka M, Kinashi T (2004) Rap1-mediated lymphocyte function-associated antigen-1 activation by the T cell antigen receptor is dependent on phospholipase C-gamma1. J Biol Chem 279:11875–11881

    Article  PubMed  CAS  Google Scholar 

  28. Katagiri K, Hattori M, Minato N, Irie S, Takatsu K, Kinashi T (2000) Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol Cell Biol 20:1956–1969

    Article  PubMed  CAS  Google Scholar 

  29. Kim M, Carman CV, Springer TA (2003) Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301:1720–1725

    Article  PubMed  CAS  Google Scholar 

  30. Kinashi T (2005) Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 5:546–559

    Article  PubMed  CAS  Google Scholar 

  31. Klarlund JK, Tsiaras W, Holik JJ, Chawla A, Czech MP (2000) Distinct polyphosphoinositide binding selectivities for pleckstrin homology domains of GRP1-like proteins based on diglycine versus triglycine motifs. J Biol Chem 275:32816–32821

    Article  PubMed  CAS  Google Scholar 

  32. Kliche S, Nagel W, Kremmer E, Atzler C, Ege A, Knorr T, Koszinowski U, Kolanus W, Haas J (2000) Cellular Transformation by Human Herpesvirus 8 (HHV-8) Kaposin A is mediated through membrane recruitment of Cytohesin-1. Molecular Cell 7:833–843

    Article  Google Scholar 

  33. Koga S, Yogo K, Yoshikawa K, Samori H, Goto M, Uchida T, Ishida N, Takeya T (2005) Physical and functional association of c-Src and adhesion and degranulation promoting adaptor protein (ADAP) in osteoclastogenesis in vitro. J Biol Chem 280:31564–31571

    Article  PubMed  CAS  Google Scholar 

  34. Kolanus W, Nagel W, Schiller B, Zeitlmann L, Godar S, Stockinger H, Seed B (1996) Alpha L beta 2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell 86:233–242

    Article  PubMed  CAS  Google Scholar 

  35. Kolanus W, Seed B (1997) Integrins and inside-out signal transduction: converging signals from PKC and PIP3. Curr Opin Cell Biol 9:725–731

    Article  PubMed  CAS  Google Scholar 

  36. Kondo A, Hashimoto S, Yano H, Nagayama K, Mazaki Y, Sabe H (2000) A new paxillin-binding protein, PAG3/Papalpha/KIAA0400, bearing an ADP-ribosylation factor GTPase-activating protein activity, is involved in paxillin recruitment to focal adhesions and cell migration. Mol Biol Cell 11:1315–1327

    PubMed  CAS  Google Scholar 

  37. Korthauer U, Nagel W, Davis EM, Le Beau MM, Menon RS, Mitchell EO, Kozak CA, Kolanus W, Bluestone JA (2000) Anergic T lymphocytes selectively express an integrin regulatory protein of the cytohesin family. J Immunol 164:308–318

    PubMed  CAS  Google Scholar 

  38. Monier S, Chardin P, Robineau S, Goud B (1998) Overexpression of the ARF1 exchange factor ARNO inhibits the early secretory pathway and causes the disassembly of the Golgi complex. J Cell Sci 111:3427–3436

    PubMed  CAS  Google Scholar 

  39. Nagel W, Schilcher P, Zeitlmann L, Kolanus W (1998a) The PH domain and the polybasic c domain of cytohesin-1 cooperate specifically in plasma membrane association and cellular function. Mol Biol Cell 9:1981–1994

    PubMed  CAS  Google Scholar 

  40. Nagel W, Zeitlmann L, Schilcher P, Geiger C, Kolanus J, Kolanus W (1998b) Phosphoinositide 3-OH Kinase Activates The Beta2 Integrin Adhesion Pathway And Induces Membrane Recruitment Of Cytohesin-1. J Biol Chem 273:14853–14861

    Article  PubMed  CAS  Google Scholar 

  41. Nevrivy DJ, Peterson VJ, Avram D, Ishmael JE, Hansen SG, Dowell P, Hruby DE, Dawson MI, Leid M (2000) Interaction Of GRASP, A Protein Encoded By A Novel Retinoic Acid-Induced Gene, With Members Of The Cytohesin Family Of Guanine Nucleotide Exchange Factors. J Biol Chem 275:16827–16836

    Article  PubMed  CAS  Google Scholar 

  42. O'Toole TE, Mandelman D, Forsyth J, Shattil SJ, Plow EF, Ginsberg MH (2001) Modulation of the affinity of integrin alpha IIb beta 3 (GPIIb-IIIa) by the cytoplasmic domain of alpha IIb. Science 254:845–847

    Article  Google Scholar 

  43. Perez O, Mitchell D, Jager G, South S, Murriel C, Mcbride J, Herzenberg LA, Kinoshita S, Nolan GP (2003) Leukocyte Functional Antigen 1 Lowers T Cell Activation Thresholds And Signaling Through Cytohesin-1 And Jun-Activating Binding Protein 1. Nat Immunol 4:1083–1092

    Article  PubMed  CAS  Google Scholar 

  44. Peterson EJ (2003) The TCR ADAPts to integrin-mediated cell adhesion. Immunol Rev 192:113–121

    Article  PubMed  CAS  Google Scholar 

  45. Peterson EJ, Woods ML, Dmowski SA, Derimanov G, Jordan MS, Wu JN, Myung PS, Liu QH, Pribila JT, Freedman BD, Shimizu Y, Koretzky GA (2001) Coupling of the TCR to integrin activation by Slap-130/Fyb. Science 293:2263–2265

    Article  PubMed  CAS  Google Scholar 

  46. Ralston KJ, Hird SL, Zhang X, Scott JL, Jin B, Thorne RF, Berndt MC, Boyd AW, Burns GF (2004) The LFA-1-associated molecule PTA-1 (CD226) on T cells forms a dynamic molecular complex with protein 4.1G and human discs large. J Biol Chem 279:33816–33828

    Article  PubMed  CAS  Google Scholar 

  47. Reedquist KA, Ross E, Koop EA, Wolthuis RM, Zwartkruis FJ, van Kooyk Y, Salmon M, Buckley CD, Bos JL (2000) The small GTPase, Rap1, mediates CD31-induced integrin adhesion. J Cell Biol 148:1151–1158

    Article  PubMed  CAS  Google Scholar 

  48. Santy LC, Casanova JE (2001) Activation of ARF6 By ARNO Stimulates Epithelial Cell Migration Through Downstream Activation Of Both Rac1 And Phospholipase DJ. Cell Biol 154:599–610

    Article  CAS  Google Scholar 

  49. Santy LC, Casanova JE (2002) Gtpase Signaling: Bridging The GAP Between ARF And Rho. Curr Biol 12:R360–R362

    Article  PubMed  CAS  Google Scholar 

  50. Sebzda E, Bracke M, Tugal T, Hogg N, Cantrell DA (2003) Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nat Immunol 3(3):251–258

    Article  CAS  Google Scholar 

  51. Shamri R, Grabovsky V, Gauguet JM, Feigelson S, Manevich E, Kolanus W, Robinson MK, Staunton DE, von Andrian UH, Alon R (2005) Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat Immunol 6(5):497–506

    Article  PubMed  CAS  Google Scholar 

  52. Shibuya K, Shirakawa J, Kameyama T, Honda S, Tahara-Hanaoka S, Miyamoto A, Onodera M, Sumida T, Nakauchi H, Miyoshi H, Shibuya A (2003) CD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation. J Exp Med 198(12):1829–1839

    Article  PubMed  CAS  Google Scholar 

  53. Shibuya K, Lanier LL, Phillips JH, Ochs HD, Shimizu K, Nakayama E, Nakauchi H, Shibuya A (1999) Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 11(5):615–623

    Article  PubMed  CAS  Google Scholar 

  54. Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, Ginsberg MH, Calderwood DA (2003) Talin binding to integrin beta tails: a final common step in integrin activation. Science 302:103–106

    Article  PubMed  CAS  Google Scholar 

  55. Tang P, Cheng TP, Agnello D, Wu CY, Hissong BD, Watford WT, Ahn HJ, Galon J, Moss J, Vaughan M, Oshea JJ, Gadina M (2002) Cybr, A Cytokine-Inducible Protein That Binds Cytohesin-1 And Regulates Its Activity. Proc Natl Acad Sci USA 99:2625–2629

    Article  PubMed  CAS  Google Scholar 

  56. Tohyama Y, Katagiri K, Pardi R, Lu C, Springer TA, Kinashi T (2003) The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration. Mol Biol Cell 14(6):2570–2582

    Article  PubMed  CAS  Google Scholar 

  57. Wang H, Moon EY, Azouz A, Wu X, Smith A, Schneider H, Hogg N, Rudd CE (2003) SKAP-55 regulates integrin adhesion and formation of T cell-APC conjugates. Nat Immunol 4:366–374

    Article  PubMed  CAS  Google Scholar 

  58. Wright MM, McMaster CR (2002) Phospholipid synthesis, diacylglycerol compartmentation, and apoptosis. Biol Res 35:223–229

    Article  PubMed  CAS  Google Scholar 

  59. Weber KS, Weber C, Ostermann G, Dierks H, Nagel W, Kolanus W (2001) Cytohesin-1 Is A Dynamic Regulator Of Distinct LFA-1 Functions In Leukocyte Arrest And Transmigration Triggered By Chemokines. Curr Biol 11:1969–1974

    Article  PubMed  CAS  Google Scholar 

  60. Zaal KJ, Smith CL, Polishchuk RS, Altan N, Cole NB, Ellenberg J, Hirschberg K, Presley JF, Roberts TH, Siggia E, Phair RD, Lippincott-Schwartz J (1999) Golgi membranes are absorbed into and reemerge from the ER during mitosis. Cell 99:589–601

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Life and Medical Sciences Institute (LIMES), Molecular Immune and Cell Biology Program Unit, Laboratory of Molecular Immunology, University of Bonn, Karlrobert-Kreiten Str. 13, 53115, Bonn, Germany

    Bettina Kellersch & Waldemar Kolanus

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  1. Bettina Kellersch
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  2. Waldemar Kolanus
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Correspondence to Waldemar Kolanus .

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Eckart D. Gundelfinger Constanze I. Seidenbecher Burkhart Schraven

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© 2006 Springer-Verlag Berlin Heidelberg

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Kellersch, B., Kolanus, W. (2006). Membrane-Proximal Signaling Events in Beta-2 Integrin Activation. In: Gundelfinger, E.D., Seidenbecher, C.I., Schraven, B. (eds) Cell Communication in Nervous and Immune System. Results and Problems in Cell Differentiation, vol 43. Springer, Berlin, Heidelberg . https://doi.org/10.1007/400_024

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