Neutrophil activation via β₂ integrins (CD11/CD18): Molecular mechanisms and clinical implications

Summary

Polymorphonuclear neutrophils (PMN) are key components of the innate immunity and their efficient recruitment to the sites of lesion is a prerequisite for acute inflammation. Signaling via adhesion molecules of the β₂ integrin family (CD11/CD18) plays an essential role for PMN recruitment and activation during inflammation. In this review, we will focus on the non-receptor tyrosine kinase Syk, an important downstream signaling component of β₂ integrins that is required for the control of different PMN functions including adhesion,migration and phagocytosis. The exploration of β₂ integrin-mediated Syk activation provided not only novel insights into the control of PMN functions but also led to the identification of Syk as a new molecular target for therapeutic intervention during inflammatory diseases.

Keywords

Integrins - inflammation - leukocyte trafficking / recruitment - signal transduction

• References

• 1 Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006; 6: 173-182.
• 2 Schmid-Schonbein GW. Analysis of inflammation. Annu Rev Biomed Eng 2006; 8: 93-131.
• 3 Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 2007; 127: 514-525.
• 4 Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860-867.
• 5 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edgedsword. Nat Rev Immunol 2006; 6: 508-519.
• 6 Simon SI, Green CE. Molecular mechanics and dynamics of leukocyte recruitment during inflammation. Annu Rev Biomed Eng 2005; 7: 151-185.
• 7 Nourshargh S, Marelli-Berg FM. Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol 2005; 26: 157-165.
• 8 Anderson DC, Springer TA. Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins. Annu Rev Med 1987; 38: 175-194.
• 9 Bowen TJ, Ochs HD, Altman LC. et al. Severe recurrent bacterial infections associated with defective adherence and chemotaxis in two patients with neutrophils deficient in acell-associated glycoprotein. J Pediatr 1982; 101: 932-940.
• 10 Anderson DC, Schmalsteig FC, Finegold MJ. et al. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis 1985; 152: 668-689.
• 11 Walzog B, Scharffetter-Kochanek K, Gaehtgens P. Impairment of neutrophil emigration in CD18-null mice. Am J Physiol 1999; 276: G1125-1130.
• 12 Sixt M, Bauer M, Lammermann T. et al. β₁ integrins: zip codes and signaling relay for blood cells. Curr Opin Cell Biol 2006; 18: 482-90.
• 13 Luo BH, Carman CV, Springer TA. Structural Basis of Integrin Regulationand Signaling. Annu Rev Immunol 2007; 619-647.
• 14 Walzog B, Offermanns S, Zakrzewicz A. et al. β₂ integrins mediate protein tyrosine phosphorylation in human neutrophils. J Leukoc Biol 1996; 59: 747-753.
• 15 Yan SR, Huang M, Berton G. Signaling by adhesion in human neutrophils: activation of the p72syk tyrosine kinase and formation of proteincomplexes containing p72syk and Src family kinases in neutrophils spreading over fibrinogen. J Immunol 1997; 158: 1902-1910.
• 16 Plow EF, Haas TA, Zhang L. et al. Ligand binding to integrins. J Biol Chem 2000; 275: 21785-21788.
• 17 Walzog B, Schuppan D, Heimpel C. et al. The leukocyte integrin Mac-1 (CD11b/CD18) contributes to binding of human granulocytes to collagen. Exp Cell Res 1995; 218: 28-38.
• 18 Mócsai A, Zhou M, Meng F. et al. Syk is required for integrin signaling in neutrophils. Immunity 2002; 16: 547-558.
• 19 Willeke T, Schymeinsky J, Prange P. et al. A role for Syk-kinase in the control of the binding cycle of the β₂ integrins (CD11/CD18) in human polymorphonuclear neutrophils. J Leukoc Biol 2003; 74: 260-269.
• 20 Woodside DG, Obergfell A, Talapatra A. et al. The N-terminal SH2 domains of Syk and ZAP-70 mediate phosphotyrosine-independent binding to integrin beta cytoplasmic domains. J Biol Chem 2002; 277: 39401-39408.
• 21 Sada K, Takano T, Yanagi S. et al. Structure and function of Syk protein-tyrosine kinase. J Biochem (Tokyo) 2001; 130: 177-186.
• 22 Mócsai A, Zhang H, Jakus Z. et al. G-protein-coupledreceptor signaling in Syk-deficient neutrophils and mast cells. Blood 2003; 101: 4155-4163.
• 23 Zioncheck TF, Harrison ML, Isaacson CC. et al. Generation of an active protein-tyrosine kinase from lymphocytes by proteolysis. J Biol Chem 1988; 263: 19195-19202.
• 24 Cheng AM, Rowley B, Pao W. et al. Syk tyrosine kinase required for mouse viability and B-cell development. Nature 1995; 378: 303-306.
• 25 Turner M, Mee PJ, Costello PS. et al. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 1995; 378: 298-302.
• 26 Turner M, Schweighoffer E, Colucci F. et al. Tyrosine kinase SYK: essential functions for immunoreceptor signalling. Immunol Today 2000; 21: 148-154.
• 27 Gilfillan AM, Tkaczyk C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 2006; 6: 218-230.
• 28 Abtahian F, Guerriero A, Sebzda E. et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 2003; 299: 247-251.
• 29 Sebzda E, Hibbard C, Sweeney S. et al. Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Dev Cell 2006; 11: 349-361.
• 30 Fuortes M, Jin WW, Nathan C. Adhesion-dependent protein tyrosine phosphorylation in neutrophils treated with tumornecrosis factor. J Cell Biol 1993; 120: 777-784.
• 31 Laudanna C, Rossi F, Berton G. Effect of inhibitors of distinct signalling pathways on neutrophil O₂ ^- generation in response to tumor necrosis factor-α, and antibodies against CD18 and CD11a: evidence for a common and unique pattern of sensitivity to wortmannin and protein tyrosine kinase inhibitors. Biochem Biophys Res Commun 1993; 190: 935-940.
• 32 Berton G, Fumagalli L, Laudanna C. et al. β₂ integrin-dependent protein tyrosine phosphorylation and activation of the FGR protein tyrosine kinase in human neutrophils. J Cell Biol 1994; 126: 1111-1121.
• 33 Yan SR, Fumagalli L, Berton G. Activation of p58c-fgr and p53/56lyn in adherent human neutrophils: evidence for a role of divalent cations in regulating neutrophil adhesion and protein tyrosine kinase activities. J Inflamm 1995; 45: 297-311.
• 34 Lowell CA, Fumagalli L, Berton G. Deficiency of Src family kinases p59/61^hck and p58^c-fgr results in defective adhesion-dependent neutrophil functions. J Cell Biol 1996; 133: 895-910.
• 35 Mócsai A, Ligeti E, Lowell CA. et al. Adhesion-dependent degranulation of neutrophils requires the Src familykinases Fgrand Hck. J Immunol 1999; 162: 1120-1126.
• 36 Pereira S, Lowell CA. The Lyn tyrosine kinase negatively regulates neutrophil integrin signaling. J Immunol 2003; 171: 1319-1327.
• 37 Pereira S, Zhou M, Mócsai A. et al. Resting murine neutrophils express functional α₄ integrins that signal through Src familykinases. J Immunol 2001; 166: 4115-4123.
• 38 Bu JY, Shaw AS, Chan AC. Analysis of the interaction of ZAP-70 and Syk protein-tyrosine kinases with the T-cell antigen receptor by plasmon resonance. Proc Natl Acad Sci USA 1995; 92: 5106-5110.
• 39 Chen T, Repetto B, Chizzonite R. et al. Interaction of phosphorylated FceRIg immunoglobulin receptor tyrosine activation motif-based peptides with dual and single SH2 domains of p72^syk. Assessment of binding parameters and real time binding kinetics. J Biol Chem 1996; 271: 25308-25315.
• 40 Abtahian F, Bezman N, Clemens R. et al. Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells. Mol Cell Biol 2006; 26: 6936-6949.
• 41 Mócsai A, Abram CL, Jakus Z. et al. Integrinsignaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat Immunol 2006; 7: 1326-1333.
• 42 Fodor S, Jakus Z, Mócsai A. ITAM-based signaling beyond the adaptive immune response. Immunol Lett 2006; 104: 29-37.
• 43 Zhou MJ, Brown EJ. CR3 (Mac-1, α_Mβ₂, CD11b/CD18)and FcγRIII cooperate in generation of a neutrophil respiratory burst: requirement for FcgRIII and tyrosine phosphorylation. J Cell Biol 1994; 125: 1407-1416.
• 44 Jakus Z, Berton G, Ligeti E. et al. Responses of neutrophils to anti-integrin antibodies depends on costimulation through low affinity FcγRs: full activation requires both integrin and nonintegrin signals. J Immunol 2004; 173: 2068-2077.
• 45 Newbrough SA, Mócsai A, Clemens RA. et al. SLP-76 regulates Fcγ receptor and integrin signaling in neutrophils. Immunity 2003; 19: 761-769.
• 46 Turner M, Billadeau DD. Vav proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol 2002; 2: 476-486.
• 47 Gakidis MA, Cullere X, Olson T. et al. Vav GEFs are required for β₂ integrin-dependent functions of neutrophils. J Cell Biol 2004; 166: 273-282.
• 48 Zhang J, Billingsley ML, Kincaid RL. et al. Phosphorylation of Syk activation loop tyrosines is essential for Syk function. An in vivo study using a specificanti Syk activation loop phosphotyrosine antibody. J Biol Chem 2000; 275: 35442-35447.
• 49 Berton G, Mocsai A, Lowell CA. Src and Syk kinases: key regulators of phagocytic cell activation. Trends Immunol 2005; 26: 208-214.
• 50 Larbolette O, Wollscheid B, Schweikert J. et al. SH3P7 is a cytoskeleton adapter protein and is coupled to signal transduction from lymphocyte antigen receptors. Mol Cell Biol 1999; 19: 1539-1546.
• 51 Moon KD, Post CB, Durden DL. et al. Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase. J Biol Chem 2005; 280: 1543-1551.
• 52 Yankee TM, Keshvara LM, Sawasdikosol S. et al. Inhibition of signaling through the B cell antigen receptor by the protooncogene product, c-Cbl, requires Syk tyrosine 317 and the c-Cbl phosphotyrosine-binding domain. J Immunol 1999; 163: 5827-5835.
• 53 Rebecchi MJ, Pentyala SN. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev 2000; 80: 1291-1335.
• 54 Jones NP, Peak J, Brader S. et al. PLCgamma1 is essential for early events in integrin signalling required for cell motility. J Cell Sci 2005; 118: 2695-2706.
• 55 Mouneimne G, Soon L, Des Marais V. et al. Phospholipase C and c of ilin are required for carcinoma cell directionality in response to EGF stimulation. J Cell Biol 2004; 166: 697-708.
• 56 Hornstein I, Alcover A, Katzav S. Vav proteins, masters of the world of cytoskeleton organization. Cell Signal 2004; 16: 1-11.
• 57 Lopez-Lago M, Lee H, Cruz C. et al. Tyrosine phosphorylation mediates both activation and downmodulation of the biological activity of Vav. Mol Cell Biol 2000; 20: 1678-1691.
• 58 Koretzky GA, Abtahian F, Silverman MA. SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 2006; 6: 67-78.
• 59 Obergfell A, Judd BA, del Pozo MA. et al. The molecular adapter SLP-76 relays signals from platelet integrin alphaIIbbeta3 to the actin cytoskeleton. J Biol Chem 2001; 276: 5916-5923.
• 60 Schmidt MH, Dikic I. The Cbl interactome and its functions. Nat Rev Mol Cell Biol 2005; 6: 907-919.
• 61 Rao N, Ghosh AK, Ota S. et al. The non-receptor tyrosine kinase Syk is a target of Cbl-mediated ubiquity-lation upon B-cell receptor stimulation. EMBO J 2001; 20: 7085-7095.
• 62 Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 1991; 67: 1033-1036.
• 63 Ley K. Integration of inflammatory signals by rolling neutrophils. Immunol Rev 2002; 186: 8-18.
• 64 Abbal C, Lambelet M, Bertaggia D. et al. Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions. Blood 2006; 108: 3352-3359.
• 65 Urzainqui A, Serrador JM, Viedma F. et al. ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1. Immunity 2002; 17: 401-412.
• 66 Ivetic A, Ridley AJ. Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes. Immunology 2004; 112: 165-176.
• 67 Arfors KE, Lundberg C, Lindbom L. et al. A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood 1987; 69: 338-340.
• 68 von Andrian UH, Chambers JD, McEvoy LM. et al. Two-step model of leukocyte-endothelial cell interaction in inflammation:: distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo. Proc Natl Acad Sci USA 1991; 88: 7538-7542.
• 69 Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep para-digm. Cell 1994; 76: 301-314.
• 70 Ley K, Zarbock A. Hold on to your endothelium: postarrest steps of the leukocytea dhesion cascade. Immunity 2006; 25: 185-187.
• 71 Burns S, Cory GO, Vainchenker W. et al. Mechanisms of WASp-mediated hematologic and immunologic disease. Blood 2004; 104: 3454-3462.
• 72 Zhang H, Schaff UY, Green CE. et al. Impaired integrin-dependent function in Wiskott-Aldrich syndrome protein-deficient murine and human neutrophils. Immunity 2006; 25: 285-295.
• 73 Anton IM, Jones GE. WIP: a multifunctional protein involved in actin cytoskeleton regulation. EMBO 2006; 85: 295-304.
• 74 Anton IM, de la Fuente MA, Sims TN. et al. WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cellactivation. Immunity 2002; 16: 193-204.
• 75 Kettner A, Kumar L, Anton IM. et al. WIP regulates signaling via the high affinity receptor for immunoglobulin Einmast cells. J Exp Med 2004; 199: 357-368.
• 76 Ding ZM, Babensee JE, Simon SI. et al. Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol 1999; 163: 5029-5038.
• 77 Coxon A, Rieu P, Barkalow FJ. et al. A novel role for the β₂ integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity 1996; 5: 653-666.
• 78 Phillipson M, Heit B, Colarusso P. et al. Intraluminal crawling of neutrophils to emigration sites: a mo-lecularly distinct process from adhesion in the recruitment cascade. J Exp Med 2006; 203: 2569-2575.
• 79 Schenkel AR, Mamdouh Z, Muller WA. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 2004; 5: 393-400.
• 80 Schreiber TH, Shinder V, Cain DW. et al. Shear flow-dependent integration of apical and subendothe-lial chemokines in T-cell transmigration: implications for locomotion and the multistep paradigm. Blood 2007; 109: 1381-1386.
• 81 Schymeinsky J, Sindrilaru A, Frommhold D. et al. The Vav binding site of the non-receptor tyrosine kinase Syk at Tyr348 is critical for β₂ integrin (CD11/CD18)-mediated neutrophil migration. Blood 2006; 108: 3919-3927.
• 82 Hirahashi J, Mekala D, Van Ziffle J. et al. Mac-1 signaling via Src-familyand Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 2006; 25: 271-283.
• 83 Peters T, Sindrilaru A, Hinz B. et al. Wound-healing defect of CD18(-/-)micedue to a decrease in TGF-β1 and myofibroblast differentiation. EMBO J 2005; 24: 3400-3410.
• 84 Schruefer R, Sulyok S, Schymeinsky J. et al. The proangiogenic capacity of polymorphonuclear neutrophils delineated by microarray technique and by measurement of neovascularization in wounded skin of CD18-deficient mice. J Vasc Res 2006; 43: 1-11.
• 85 Chavakis E, Aicher A, Heeschen C. et al. Role of β₂-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 2005; 201: 63-72.
• 86 Yan SR, Berton G. Antibody-induced engagement of β₂ integrins in human neutrophils causes a rapid redistribution of cytoskeletal proteins, Src-family tyrosine kinases, and p72syk that precedes de novo actin polymerization. J Leukoc Biol 1998; 64: 401-408.
• 87 Walzog B, Seifert R, Zakrzewicz A. et al. Cross-linking of CD18 in human neutrophils induces an increase of intracellular free Ca²⁺, exocytosis of azurophilic granules, quantitative up-regulation of CD18, shedding of L-selectin, and actin polymerization. J Leukoc Biol 1994; 56: 625-635.
• 88 Kessels MM, Engqvist-Goldstein AE, Drubin DG. et al. Mammalian Abp1, a signal-responsive F-actin-binding protein, links the actin cytoskeleton to endocytosis via the GTPase dynamin. J Cell Biol 2001; 153: 351-366.
• 89 Stephens L, Ellson C, Hawkins P. Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Curr Opin Cell Biol 2002; 14: 203-213.
• 90 Giagulli C, Ottoboni L, Caveggion E. et al. The Src family kinases Hck and Fgr are dispensable for inside-out, chemoattractant-induced signaling regulating β₂ integrin affinity and valency in neutrophils, but are required for β₂ integrin-mediated outside-in signaling involved in sustained adhesion. J Immunol 2006; 177: 604-611.
• 91 Miranti CK, Leng L, Maschberger P. et al. Identification of a novel integrin signaling pathway involving the kinase Syk and the guanine nucleotide exchange factor Vav1. Curr Biol 1998; 8: 1289-1299.
• 92 Vicente-Manzanares M, Cruz-Adalia A, Martin Cofreces NB. et al. Control of lymphocyte shape and the chemotactic response by the GTP exchange factor Vav. Blood 2005; 105: 3026-3034.
• 93 Vedham V, Phee H, Coggeshall KM. Vav activation and function as a rac guanine nucleotide exchange factor in macrophage colony-stimulating factor-induced macrophage chemotaxis. Mol Cell Biol 2005; 25: 4211-4220.
• 94 Bokoch GM. Regulation of innate immunity by Rho GTPases. Trends Cell Biol 2005; 15: 163-171.
• 95 Pradip D, Peng X, Durden DL. Rac2 specificity in macrophage integrin signaling: potential role for Syk kinase. J Biol Chem 2003; 278: 41661-41669.
• 96 Sun CX, Downey GP, Zhu F. et al. Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 2004; 104: 3758-3765.
• 97 Barber MA, Welch HC. PI3K and RAC signalling in leukocyte and cancer cell migration. Bull Cancer 2006; 93: E44-52.
• 98 Dib K, Melander F, Axelsson L. et al. Down-regulation of Rac activity during b₂ integrin-mediated adhesion of human neutrophils. J Biol Chem 2003; 278: 24181-24188.
• 99 Srinivasan S, Wang F, Glavas S. et al. Rac and Cdc42 play distinct roles in regulating PI (3,4,5) P3 and polarity during neutrophil chemotaxis. J Cell Biol 2003; 160: 375-385.
• 100 Worthylake RA, Lemoine S, Watson JM. et al. RhoA is required for monocyte tail retraction during transendothelial migration. J Cell Biol 2001; 154: 147-160.
• 101 Worthylake RA, Burridge K. RhoA and ROCK promote migration by limiting membrane protrusions. J Biol Chem 2003; 278: 13578-13584.
• 102 Shi Y, Tohyama Y, Kadono T. et al. Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis. Blood 2006; 107: 4554-4562.
• 103 Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 2003; 72: 743-781.
• 104 Obergfell A, Eto K, Mocsai A. et al. Coordinate interactions of Csk, Src, and Syk kinases with α_IIbβ₃ initiate integrin signaling to the cytoskeleton. J Cell Biol 2002; 157: 265-275.
• 105 Li Z, Hannigan M, Mo Z. et al. Directional sensing requires G_βγ-mediated PAK1 and PIX α-dependent activation of Cdc42. Cell 2003; 114: 215-227.
• 106 Dharmawardhane S, Brownson D, Lennartz M. et al. Localization of p21-activated kinase 1(PAK1)to pseudopodia, membrane ruffles, and phagocytic cups in activated human neutrophils. J Leukoc Biol 1999; 66: 521-527.
• 107 Huang R, Lian JP, Robinson D. et al. Neutrophils stimulated with a variety of chemoattractants exhibit rapid activation of p21-activated kinases (Paks): separate signalsare required for activationand inactivation of paks. Mol Cell Biol 1998; 18: 7130-7138.
• 108 Mouneimne G, Des Marais V, Sidani M. et al. Spatial and temporal controlof cofilin activity is required for directional sensing during chemotaxis. Curr Biol 2006; 16: 2193-2205.
• 109 Nishita M, Tomizawa C, Yamamoto M. et al. Spatial and temporal regulationofc of ilin activity by LIM kinase and Slingshot is critical for directional cell migration. J Cell Biol 2005; 171: 349-359.
• 110 Des Marais V, Ghosh M, Eddy R. et al. Cofilin takes the lead. J Cell Sci 2005; 118: 19-26.
• 111 Guo D, Tan YC, Wang D. et al. A Rac-cGMP signaling pathway. Cell 2007; 128: 341-355.
• 112 Elferink JG, Van Uffelen BE. The role of cyclic nucleotides in neutrophil migration. Gen Pharmacol 1996; 27: 387-393.
• 113 Sato Y. Modulation of PMN-endothelial cells interactions by cyclic nucleotides. Curr Pharm Des 2004; 10: 163-170.
• 114 Jenei V, Deevi RK, Adams CA. et al. Nitric oxide produced in response to engagement of β₂ integrins on human neutrophils activates the monomeric GTPases Rap1 and Rap2 and promotes adhesion. J Biol Chem 2006; 281: 35008-35020.
• 115 Kubes P, Kurose I, Granger DN. N Odonors prevent integrin-induced leukocyte adhesion but not P-selectin-dependent rolling in postischemic venules. Am J Physiol 1994; 267: H931-937.
• 116 Deane JA, Fruman DA. Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu Rev Immunol 2004; 22: 563-598.
• 117 Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7: 606-619.
• 118 Van Haastert PJ, Devreotes PN. Chemotaxis: signalling the way forward. Nat Rev Mol Cell Biol 2004; 5: 626-634.
• 119 Wang F, Herzmark P, Weiner OD. et al. Lipid prod-ucts of PI(3) Ks maintain persistent cell polarity and directed motility in neutrophils. Nat Cell Biol 2002; 4: 513-518.
• 120 Beitz LO, Fruman DA, Kurosaki T. et al. SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling. J Biol Chem 1999; 274: 32662-32666.
• 121 von Willebrand M, Williams S, Tailor P. et al. Phosphorylation of the Grb 2- and phosphatidylinositol 3-kinase p85-binding p36/38 by Syk in Lck-negative T cells. Cell Signal 1998; 10: 407-413.
• 122 Axelsson L, Hellberg C, Melander F. et al. Clustering of β₂-integrins on human neutrophils activates dual signaling pathways to Ptd Ins 3-kinase. Exp Cell Res 2000; 256: 257-263.
• 123 Gao XP, Zhu X, Fu J. et al. Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation. J Biol Chem 2007; 282: 6116-6125.
• 124 Li B, Allendorf DJ, Hansen R. et al. Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway. J Immunol 2006; 177: 1661-1669.
• 125 Wettschureck N, Offermanns S. Mammalian G proteins and theircelltype specific functions. Phys Rev 2005; 85: 1159-1204.
• 126 O’Neill LA. Targetingsignal transduction as a strategy to treat inflammatory diseases. Nat Rev Drug Discov 2006; 5: 549-563.
• 127 Luster AD, Alon R, von Andrian UH. Immune cell migrationin in flammation: present and future therapeutic targets. Nat Immunol 2005; 6: 1182-1190.
• 128 Yonekawa K, Harlan JM. Targeting leukocyte integrins in human diseases. J Leukoc Biol 2005; 77: 129-140.
• 129 Braselmann S, Taylor V, Zhao H. et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006; 319: 998-1008.
• 130 Rossi AB, Herlaar E, Braselmann S. et al. Identification of the Syk kinase inhibitor R112 by a human mast cell screen. J Allergy Clin Immunol 2006; 118: 749-755.
• 131 Meltzer EO, Berkowitz RB, Grossbard EB. An intranasal Syk-kinase inhibitor (R112) improves the symptons of seasonal allergic rhinitis in a park environment. J Allergy Clin Immunol 2005; 115: 791-796.
• 132 Stenton GR, Ulanova M, Dery RE. et al. Inhibition of allergic inflammation in the airways using aerosolized antisense to Syk kinase. J Immunol 2002; 169: 1028-1036.