Pathway Map Details

Inhibitory action of Lipoxins on neutrophil migration

view in full size
| open in MetaCore

Object list (links open in MetaCore):

PLD1, Rac1, Cofilin, Myosin II, IL-8,, PI3K reg class IB (p101), IL8RB, Rac2, O(2)(-), PAK1, PDPK1,, MRLC, 3.1.3.-, MELC, ICAM1, Cl(-) extracellular region, Actin cytoskeletal, Arp2/3, chloride ion = chloride ion, IL8RA, Presqualene diphosphate,, MLCP (reg), PPAPDC2, LIMK1, Phosphatidic acid, Hydrogen peroxide, MYLK1, MLCP (cat), ITGB2, G-protein beta/gamma, CFTR, PKC-zeta, Lipoxin A4, PI3K cat class IB (p110-gamma), Cl(-) cytosol, 1-(1,2-diacyl-glycerol 3-phospho)-inositol 4-phosphate, 1,2-diacyl-glycerol 3-phosphate, PIP5KI, MLCK, Alpha-actinin, PREX1, AKT, ERK1/2, 15-epi-LXA4, G-protein alpha-i family, Presqualene monophosphate, alpha-L/beta-2 integrin, LTBR1, Talin, FPRL1, Leukotriene B4 , PtdIns(4,5)P2,, PtdIns(3,4,5)P3


Inhibitory action of Lipoxins on neutrophil migration

Deregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways in cystic fibrosis (CF). In normal tissues, lipoxins are endogenous anti-inflammatory lipid mediators in regulation of neutrophilic inflammation [1]. In CF, production of lipoxins is impaired [2], [3].

One striking feature of CF airways is the progressive accumulation of neutrophils. This "acute inflammation" never converts to a more "chronic" pattern. There is certainly an excess of chemoattractants such as Interleukin-8 ( IL-8 ) and Leukotriene B4 recovered in bronchoalveolar lavage fluid. When present in excess, neutrophils and their products actually impair the host's ability to clear bacterial infection [4].

Colonized by bacteria, the CF lung contains a range of potent neutrophil chemoattractants, including the host-derived inflammatory mediators IL-8 and Leukotriene B4. N-formyl-Met-Leu-Phe peptide (fMLP), produced by bacteria, usually stimulates neutrophils to migrate by a mechanism that is mediated by alpha-M/beta-2 integrin (MAC-1), whereas IL-8 and Leukotriene B4 stimulate neutrophils to migrate using an alternative, MAC-1-independent pathway, that is mediated by alpha-L/beta-2 integrin (LFA-1) [5], [6], [7], [8], [9], [10]. Over 70% of migrating neutrophils from CF patients appeared to favor this, LFA-1-dependent, migratory route [11], [12].

The circulating neutrophils from normal tissues express two receptors for IL-8, Interleukin 8 receptor alpha ( IL8RA ) and Interleukin 8 receptor beta ( IL8RB ). In contrast, neutrophils from patients with acute and chronic pulmonary inflammation have decreased expression of IL8RB, and only IL8RA is the functionally dominant receptor on these neutrophils [13], [7].

In response to infection or tissue injury, arachidonic acid produces proinflammatory Leukotriene B4 that also induces neutrophil recruitment and acute inflammation [14], [4], [15].

In normal airways, arachidonic acid also produces antiinflammatory lipoxins. Lipoxins mediate switch to chronic inflammation and promote resolution [16], [15], [17]. In CF the inflammatory response remains persistently neutrophilic that leads to tissue injury and further infection. This may be attributed to a documented defect in the generation of lipoxins [2], [3], [1].

Lipoxins are bioactive eicosanoids derived from arachidonic acid. In contrast to proinflammatory leukotrienes and prostaglandins, lipoxins ( Lipoxin A4 and 15-epi-LXA4 ) display potent antiinflammatory actions, including attenuation of neutrophil adhesion to endothelial cells [18], [1].

IL-8, Leukotriene B4 and Lipoxins ( Lipoxin A4 and 15-epi-LXA4 ) interact with highly specific and distinct G protein-coupled membrane receptors [19] [20], to evoke opposing leukocyte responses, including Lipoxin-induced inhibition of chemoattractant-initiated migration of neutrophils [21], [22], [23].

Leukotriene B4 binds to the Leukotriene B4 receptor ( LTBR1 ) that via G-protein alpha-i family and G-protein beta/gamma subunits activates Phosphatidylinositol 3-kinase ( PI3K reg class IB (p101) and PI3K cat class IB (p110-gamma) ) signaling [24], [25], [26], [27], [28], [29], [30].

IL-8 binding to IL8RA also stimulates PI3K cat class IB (p110-gamma) that phosphorylates the membrane lipid phosphatidylinositol 4,5-bisphosphate ( PtdIns(4,5)P2 ) to phosphatidylinositol 3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ) [31].

PtdIns(3,4,5)P3 recruits and activates diverse cytosolic effectors, including Phospholipase D1 ( PLD1 ) [32], 3-phosphoinositide dependent protein kinase-1 ( PDPK1 ) [33], v-Akt murine thymoma viral oncogene homologs ( AKT ) [34], [35], Protein kinase C zeta ( PKC-zeta ) [36] and Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 ( PREX1 ) [37], [38]. PREX1 is the main guanine nucleotide exchange factors for the Ras-related C3 botulinum toxin substrates 1 and 2 ( Rac1 and Rac2 ) in neutrophils [37], [31], [39], [40]. Rac1 and Rac2 stimulate the kinase activity of p21-activated kinase 1 ( PAK1 ) that is important for regulating neutrophil chemotactic responsiveness [41], [42].

PDPK1, in turn, phosphorylates and activates AKT, PKC-zeta and PAK1 [43], [44].

Lipoxin A4 and 15-epi-LXA4 interact with the Formyl peptide receptor-like 1 ( FPRL1 ) [1], [16], [17] that transduces counter-regulatory signals in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to Presqualene monophosphate upon cell activation. Phosphatidic acid phosphatase type 2 domain containing 2 ( PPAPDC2 ) is presqualene diphosphate phosphatase that converts Presqualene diphosphate to Presqualene monophosphate [45]. In human neutrophils, Leukotriene-induced LTBR1 signaling initiates a rapid decrease in Presqualene diphosphate levels, probably through PPADC2 activation, to promote proinflammatory cell response, whereas Lipoxin-induced FPRL1 signaling dramatically blocks Presqualene diphosphate turnover to Presqualene monophosphate, probably through PPADC2 inhibition, to prevent neutrophil activation [46], [15].

Presqualene diphosphate, but not Presqualene monophosphate, directly inhibits PLD1 and PI3K cat class IB (p110-gamma) [46], [47], [48], [49], [27], [15].

PLD1 hydrolyzes membrane phosphatidylcholine to generate Phosphatidic acid that is a powerful activator of PKC-zeta [50], [51], [52].

PKC-zeta has been shown to control lymphocyte alpha-L/beta-2 integrin rapid lateral mobility induced by chemokines [53], [54].

Phosphatidic acid also activates Type I phosphatidylinositol-4-phosphate 5-kinases ( PIP5KI ) that catalyze the synthesis of PtdIns(4,5)P2 [55], [56], which, in turn, mediates Talin activation of alpha-L/beta-2 integrin required for neutrophil transendothelial migration [57], [58], [59], [34]. This migration is mediated via binding of neutrophil alpha-L/beta-2 integrin to endothelial Ligand intercellular adhesion molecule-1 ( ICAM-1 ) [60], [61], [10], [54].

Cell motility also requires polarized rearrangements of the actin/myosin cytoskeleton. PAK1 regulates directional cell motility through its effects on regulatory light chains of Myosin II ( MRLC ) [62].

Downstream of Rac1, PAK1 activates LIMK1, which, in turn, regulates the actin cytoskeletal reorganization through the phosphorylation and inactivation of the actin-depolymerizing factor Cofilin [63], [64]. Actin-organizing complex ( Arp2/3 ) nucleates new Actin filaments from the sides of preexisting filaments. This interaction requires phosphorylation of Arp2/3 complex by PAK1, which promotes Actin polymerization [65].

PDPK1 and AKT also phosphorylate PAK1 that can regulate cell migration [66], [67], [68].

Leukotriene B4 can also induce neutrophil migration by Reactive oxygen species (ROS)/ Extracellular signal-regulated kinases 1 and 2 ( ERK1/2 )-linked cascade [69]. Leukotriene B4 signaling activates the NADPH oxidase that catalyzes the production of Superoxide anion ( O(2)(-) ), from which other ROS, including Hydrogen peroxide, are derived [70], [71], [72]. ERK1/2 activated by Hydrogen peroxide [73], [69] can modulate actin/myosin cytoskeleton remodeling via regulation of Myosin II phosphorylation. ERK1/2 can phosphorylate and inactivate the Myosin light chain phosphatase ( MLCP ) [74], which attenuates Myosin light chains ( MELC ) and Myosin regulatory light chains ( MRLC ) phosphorylation [75]. In addition, ERK1/2 can phosphorylate and activate Myosin light chain kinase ( MYLK1 ) [76]. Myosin II function is regulated by phosphorylation of the MRLC by Myosin light chain kinases ( MLCK ) that promotes myosin ATPase activity and polymerization of actin cables. This results in generating contractile force necessary for cell motility [77].


  1. Karp CL, Flick LM, Yang R, Uddin J, Petasis NA
    Cystic fibrosis and lipoxins. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):263-70
  2. Karp CL, Flick LM, Park KW, Softic S, Greer TM, Keledjian R, Yang R, Uddin J, Guggino WB, Atabani SF, Belkaid Y, Xu Y, Whitsett JA, Accurso FJ, Wills-Karp M, Petasis NA
    Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nature immunology 2004 Apr;5(4):388-92
  3. Takai D, Nagase T, Shimizu T
    New therapeutic key for cystic fibrosis: a role for lipoxins. Nature immunology 2004 Apr;5(4):357-8
  4. Chmiel JF, Davis PB
    State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection? Respiratory research 2003;4:8
  5. Morland CM, Morland BJ, Darbyshire PJ, Stockley RA
    Migration of CD18-deficient neutrophils in vitro: evidence for a CD18-independent pathway induced by IL-8. Biochimica et biophysica acta 2000 Jan 3;1500(1):70-6
  6. Mackarel AJ, Russell KJ, Brady CS, FitzGerald MX, O'Connor CM
    Interleukin-8 and leukotriene-B(4), but not formylmethionyl leucylphenylalanine, stimulate CD18-independent migration of neutrophils across human pulmonary endothelial cells in vitro. American journal of respiratory cell and molecular biology 2000 Aug;23(2):154-61
  7. Mackarel AJ, Russell KJ, Ryan CM, Hislip SJ, Rendall JC, FitzGerald MX, O'Connor CM
    CD18 dependency of transendothelial neutrophil migration differs during acute pulmonary inflammation. Journal of immunology (Baltimore, Md. : 1950) 2001 Sep 1;167(5):2839-46
  8. Blake KM, Carrigan SO, Issekutz AC, Stadnyk AW
    Neutrophils migrate across intestinal epithelium using beta2 integrin (CD11b/CD18)-independent mechanisms. Clinical and experimental immunology 2004 May;136(2):262-8
  9. Heit B, Colarusso P, Kubes P
    Fundamentally different roles for LFA-1, Mac-1 and alpha4-integrin in neutrophil chemotaxis. Journal of cell science 2005 Nov 15;118(Pt 22):5205-20
  10. Green CE, Schaff UY, Sarantos MR, Lum AF, Staunton DE, Simon SI
    Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium. Blood 2006 Mar 1;107(5):2101-11
  11. Brennan S, Cooper D, Sly PD
    Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin. Thorax 2001 Jan;56(1):62-4
  12. Mackarel AJ, Plant BJ, FitzGerald MX, O'Connor CM, Martin L, Elborn JS, Gallagher CG
    Cystic fibrosis sputum stimulates CD18-independent neutrophil migration across endothelial cells. Experimental lung research 2005 May;31(4):377-90
  13. Cummings CJ, Martin TR, Frevert CW, Quan JM, Wong VA, Mongovin SM, Hagen TR, Steinberg KP, Goodman RB
    Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis. Journal of immunology (Baltimore, Md. : 1950) 1999 Feb 15;162(4):2341-6
  14. Ito N, Yokomizo T, Sasaki T, Kurosu H, Penninger J, Kanaho Y, Katada T, Hanaoka K, Shimizu T
    Requirement of phosphatidylinositol 3-kinase activation and calcium influx for leukotriene B4-induced enzyme release. The Journal of biological chemistry 2002 Nov 22;277(47):44898-904
  15. Bonnans C, Levy BD
    Lipid mediators as agonists for the resolution of acute lung inflammation and injury. American journal of respiratory cell and molecular biology 2007 Feb;36(2):201-5
  16. Chiang N, Arita M, Serhan CN
    Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):163-77
  17. Serhan CN
    Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual review of immunology 2007;25:101-37
  18. Filep JG, Khreiss T, Jzsef L
    Lipoxins and aspirin-triggered lipoxins in neutrophil adhesion and signal transduction. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):257-62
  19. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN
    Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. The Journal of experimental medicine 1997 May 5;185(9):1693-704
  20. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T
    A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997 Jun 5;387(6633):620-4
  21. Lee TH, Lympany P, Crea AE, Spur BW
    Inhibition of leukotriene B4-induced neutrophil migration by lipoxin A4: structure-function relationships. Biochemical and biophysical research communications 1991 Nov 14;180(3):1416-21
  22. Serhan CN
    Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):141-62
  23. Ratjen F
    What's new in CF airway inflammation: an update. Paediatric respiratory reviews 2006;7 Suppl 1:S70-2
  24. Gaudreau R, Le Gouill C, Metaoui S, Lemire S, Stankova J, Rola-Pleszczynski M
    Signalling through the leukotriene B4 receptor involves both alphai and alpha16, but not alphaq or alpha11 G-protein subunits. The Biochemical journal 1998 Oct 1;335 ( Pt 1):15-8
  25. Tager AM, Luster AD
    BLT1 and BLT2: the leukotriene B(4) receptors. Prostaglandins, leukotrienes, and essential fatty acids 2003 Aug-Sep;69(2-3):123-34
  26. Gaudreault E, Thompson C, Stankova J, Rola-Pleszczynski M
    Involvement of BLT1 endocytosis and Yes kinase activation in leukotriene B4-induced neutrophil degranulation. Journal of immunology (Baltimore, Md. : 1950) 2005 Mar 15;174(6):3617-25
  27. Bonnans C, Fukunaga K, Keledjian R, Petasis NA, Levy BD
    Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury. The Journal of experimental medicine 2006 Apr 17;203(4):857-63
  28. Lundeen KA, Sun B, Karlsson L, Fourie AM
    Leukotriene B4 receptors BLT1 and BLT2: expression and function in human and murine mast cells. Journal of immunology (Baltimore, Md. : 1950) 2006 Sep 1;177(5):3439-47
  29. Kanda N, Watanabe S
    Leukotriene B(4) enhances tumour necrosis factor-alpha-induced CCL27 production in human keratinocytes. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2007 Jul;37(7):1074-82
  30. Pacheco P, Vieira-de-Abreu A, Gomes RN, Barbosa-Lima G, Wermelinger LB, Maya-Monteiro CM, Silva AR, Bozza MT, Castro-Faria-Neto HC, Bandeira-Melo C, Bozza PT
    Monocyte chemoattractant protein-1/CC chemokine ligand 2 controls microtubule-driven biogenesis and leukotriene B4-synthesizing function of macrophage lipid bodies elicited by innate immune response. Journal of immunology (Baltimore, Md. : 1950) 2007 Dec 15;179(12):8500-8
  31. Niggli V
    Signaling to migration in neutrophils: importance of localized pathways. The international journal of biochemistry & cell biology 2003 Dec;35(12):1619-38
  32. Lee JS, Kim JH, Jang IH, Kim HS, Han JM, Kazlauskas A, Yagisawa H, Suh PG, Ryu SH
    Phosphatidylinositol (3,4,5)-trisphosphate specifically interacts with the phox homology domain of phospholipase D1 and stimulates its activity. Journal of cell science 2005 Oct 1;118(Pt 19):4405-13
  33. Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J
    Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. The Biochemical journal 1999 Feb 1;337 ( Pt 3):575-83
  34. Di Paolo G, De Camilli P
    Phosphoinositides in cell regulation and membrane dynamics. Nature 2006 Oct 12;443(7112):651-7
  35. Manna D, Albanese A, Park WS, Cho W
    Mechanistic Basis of Differential Cellular Responses of Phosphatidylinositol 3,4-Bisphosphate- and Phosphatidylinositol 3,4,5-Trisphosphate-binding Pleckstrin Homology Domains. The Journal of biological chemistry 2007 Nov 2;282(44):32093-105
  36. Nakanishi H, Brewer KA, Exton JH
    Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. The Journal of biological chemistry 1993 Jan 5;268(1):13-6
  37. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR
    P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell 2002 Mar 22;108(6):809-21
  38. Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HC, Hawkins PT, Stephens LR
    Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits. The Journal of biological chemistry 2005 Feb 11;280(6):4166-73
  39. Welch HC, Condliffe AM, Milne LJ, Ferguson GJ, Hill K, Webb LM, Okkenhaug K, Coadwell WJ, Andrews SR, Thelen M, Jones GE, Hawkins PT, Stephens LR
    P-Rex1 regulates neutrophil function. Current biology : CB 2005 Oct 25;15(20):1867-73
  40. Hill K, Welch HC
    Purification of P-Rex1 from neutrophils and nucleotide exchange assay. Methods in enzymology 2006;406:26-41
  41. Knaus UG, Wang Y, Reilly AM, Warnock D, Jackson JH
    Structural requirements for PAK activation by Rac GTPases. The Journal of biological chemistry 1998 Aug 21;273(34):21512-8
  42. Dharmawardhane S, Brownson D, Lennartz M, Bokoch GM
    Localization of p21-activated kinase 1 (PAK1) to pseudopodia, membrane ruffles, and phagocytic cups in activated human neutrophils. Journal of leukocyte biology 1999 Sep;66(3):521-7
  43. Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS, Newton AC, Schaffhausen BS, Toker A
    Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Current biology : CB 1998 Sep 24;8(19):1069-77
  44. Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR
    A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1. The Journal of biological chemistry 2000 Jul 7;275(27):20806-13
  45. Fukunaga K, Arita M, Takahashi M, Morris AJ, Pfeffer M, Levy BD
    Identification and functional characterization of a presqualene diphosphate phosphatase. The Journal of biological chemistry 2006 Apr 7;281(14):9490-7
  46. Levy BD, Fokin VV, Clark JM, Wakelam MJ, Petasis NA, Serhan CN
    Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a 'stop' signaling switch for aspirin-triggered lipoxin A4. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999 May;13(8):903-11
  47. Levy BD, Serhan CN
    A novel polyisoprenyl phosphate signaling cascade in human neutrophils. Annals of the New York Academy of Sciences 2000 Apr;905:69-80
  48. Levy BD, Serhan CN
    Polyisoprenyl phosphates: natural antiinflammatory lipid signals. Cellular and molecular life sciences : CMLS 2002 May;59(5):729-41
  49. Levy BD, Hickey L, Morris AJ, Larvie M, Keledjian R, Petasis NA, Bannenberg G, Serhan CN
    Novel polyisoprenyl phosphates block phospholipase D and human neutrophil activation in vitro and murine peritoneal inflammation in vivo. British journal of pharmacology 2005 Oct;146(3):344-51
  50. Billah MM, Eckel S, Mullmann TJ, Egan RW, Siegel MI
    Phosphatidylcholine hydrolysis by phospholipase D determines phosphatidate and diglyceride levels in chemotactic peptide-stimulated human neutrophils. Involvement of phosphatidate phosphohydrolase in signal transduction. The Journal of biological chemistry 1989 Oct 15;264(29):17069-77
  51. Limatola C, Schaap D, Moolenaar WH, van Blitterswijk WJ
    Phosphatidic acid activation of protein kinase C-zeta overexpressed in COS cells: comparison with other protein kinase C isotypes and other acidic lipids. The Biochemical journal 1994 Dec 15;304 ( Pt 3):1001-8
  52. Limatola C, Barabino B, Nista A, Santoni A
    Interleukin 1-beta-induced protein kinase C-zeta activation is mimicked by exogenous phospholipase D. The Biochemical journal 1997 Jan 15;321 ( Pt 2):497-501
  53. Giagulli C, Scarpini E, Ottoboni L, Narumiya S, Butcher EC, Constantin G, Laudanna C
    RhoA and zeta PKC control distinct modalities of LFA-1 activation by chemokines: critical role of LFA-1 affinity triggering in lymphocyte in vivo homing. Immunity 2004 Jan;20(1):25-35
  54. Laudanna C, Alon R
    Right on the spot. Chemokine triggering of integrin-mediated arrest of rolling leukocytes. Thrombosis and haemostasis 2006 Jan;95(1):5-11
  55. Pike MC, Costello KM, Lamb KA
    IL-8 stimulates phosphatidylinositol-4-phosphate kinase in human polymorphonuclear leukocytes. Journal of immunology (Baltimore, Md. : 1950) 1992 May 15;148(10):3158-64
  56. Ishihara H, Shibasaki Y, Kizuki N, Wada T, Yazaki Y, Asano T, Oka Y
    Type I phosphatidylinositol-4-phosphate 5-kinases. Cloning of the third isoform and deletion/substitution analysis of members of this novel lipid kinase family. The Journal of biological chemistry 1998 Apr 10;273(15):8741-8
  57. Pavalko FM, LaRoche SM
    Activation of human neutrophils induces an interaction between the integrin beta 2-subunit (CD18) and the actin binding protein alpha-actinin. Journal of immunology (Baltimore, Md. : 1950) 1993 Oct 1;151(7):3795-807
  58. Martel V, Racaud-Sultan C, Dupe S, Marie C, Paulhe F, Galmiche A, Block MR, Albiges-Rizo C
    Conformation, localization, and integrin binding of talin depend on its interaction with phosphoinositides. The Journal of biological chemistry 2001 Jun 15;276(24):21217-27
  59. Calderwood DA
    Integrin activation. Journal of cell science 2004 Feb 15;117(Pt 5):657-66
  60. Seo SM, McIntire LV, Smith CW
    Effects of IL-8, Gro-alpha, and LTB(4) on the adhesive kinetics of LFA-1 and Mac-1 on human neutrophils. American journal of physiology. Cell physiology 2001 Nov;281(5):C1568-78
  61. Sarantos MR, Raychaudhuri S, Lum AF, Staunton DE, Simon SI
    Leukocyte function-associated antigen 1-mediated adhesion stability is dynamically regulated through affinity and valency during bond formation with intercellular adhesion molecule-1. The Journal of biological chemistry 2005 Aug 5;280(31):28290-8
  62. Sells MA, Boyd JT, Chernoff J
    p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. The Journal of cell biology 1999 May 17;145(4):837-49
  63. Sumi T, Matsumoto K, Nakamura T
    Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. The Journal of biological chemistry 2001 Jan 5;276(1):670-6
  64. Sumi T, Matsumoto K, Shibuya A, Nakamura T
    Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. The Journal of biological chemistry 2001 Jun 22;276(25):23092-6
  65. Dayel MJ, Mullins RD
    Activation of Arp2/3 complex: addition of the first subunit of the new filament by a WASP protein triggers rapid ATP hydrolysis on Arp2. PLoS biology 2004 Apr;2(4):E91
  66. King CC, Gardiner EM, Zenke FT, Bohl BP, Newton AC, Hemmings BA, Bokoch GM
    p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). The Journal of biological chemistry 2000 Dec 29;275(52):41201-9
  67. Zhou GL, Zhuo Y, King CC, Fryer BH, Bokoch GM, Field J
    Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration. Molecular and cellular biology 2003 Nov;23(22):8058-69
  68. Zhou GL, Tucker DF, Bae SS, Bhatheja K, Birnbaum MJ, Field J
    Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. The Journal of biological chemistry 2006 Nov 24;281(47):36443-53
  69. Woo CH, Yoo MH, You HJ, Cho SH, Mun YC, Seong CM, Kim JH
    Transepithelial migration of neutrophils in response to leukotriene B4 is mediated by a reactive oxygen species-extracellular signal-regulated kinase-linked cascade. Journal of immunology (Baltimore, Md. : 1950) 2003 Jun 15;170(12):6273-9
  70. Lrfars G, Lantoine F, Devynck MA, Palmblad J, Gyllenhammar H
    Activation of nitric oxide release and oxidative metabolism by leukotrienes B4, C4, and D4 in human polymorphonuclear leukocytes. Blood 1999 Feb 15;93(4):1399-405
  71. Serezani CH, Aronoff DM, Jancar S, Peters-Golden M
    Leukotriene B4 mediates p47phox phosphorylation and membrane translocation in polyunsaturated fatty acid-stimulated neutrophils. Journal of leukocyte biology 2005 Oct;78(4):976-84
  72. Bokoch GM, Zhao T
    Regulation of the phagocyte NADPH oxidase by Rac GTPase. Antioxidants & redox signaling 2006 Sep-Oct;8(9-10):1533-48
  73. Lee K, Esselman WJ
    Inhibition of PTPs by H(2)O(2) regulates the activation of distinct MAPK pathways. Free radical biology & medicine 2002 Oct 15;33(8):1121-32
  74. Xiao D, Longo LD, Zhang L
    Alpha1-adrenoceptor-mediated phosphorylation of MYPT-1 and CPI-17 in the uterine artery: role of ERK/PKC. American journal of physiology. Heart and circulatory physiology. 2005 Jun;288(6):H2828-35
  75. Pfitzer G
    Invited review: regulation of myosin phosphorylation in smooth muscle. Journal of applied physiology (Bethesda, Md. : 1985) 2001 Jul;91(1):497-503
  76. Cheresh DA, Leng J, Klemke RL
    Regulation of cell contraction and membrane ruffling by distinct signals in migratory cells. The Journal of cell biology 1999 Sep 6;146(5):1107-16
  77. Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA
    Regulation of cell motility by mitogen-activated protein kinase. The Journal of cell biology 1997 Apr 21;137(2):481-92