KEGG   PATHWAY: rno04670
Entry
rno04670                    Pathway                                
Name
Leukocyte transendothelial migration - Rattus norvegicus (rat)
Description
Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the "endothelial passage" through which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion.
Class
Organismal Systems; Immune system
Pathway map
rno04670  Leukocyte transendothelial migration
rno04670

Other DBs
GO: 0050900
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
315509  Jam3; junctional adhesion molecule C precursor [KO:K06785]
25021  Itgam; integrin alpha-M precursor [KO:K06461]
309684  Itgb2; integrin beta-2 precursor [KO:K06464]
619374  Jam2; junctional adhesion molecule B precursor [KO:K06735]
311144  Itga4; integrin alpha-4 [KO:K06483]
24511  Itgb1; integrin beta-1 precursor [KO:K05719]
29583  Pecam1; platelet endothelial cell adhesion molecule precursor [KO:K06471]
652929  Cd99; CD99 antigen precursor [KO:K06520]
102552482  Cd99l3; uncharacterized protein Cd99l3 [KO:K06520]
308995  Itgal; integrin alpha-L precursor [KO:K05718]
116479  F11r; junctional adhesion molecule A precursor [KO:K06089]
307618  Cdh5; cadherin-5 [KO:K06533]
290485  Cldn10; claudin-10 [KO:K06087]
290789  Cldn23; claudin-23 [KO:K06087]
298487  Cldn19; claudin-19 [KO:K06087]
300920  Cldn2; claudin-2 [KO:K06087]
304073  Cldn14; claudin-14 [KO:K06087]
304124  Cldn8; claudin-8 [KO:K06087]
304125  Cldn17; claudin-17 [KO:K06087]
304388  Cldn15; claudin-15 [KO:K06087]
304407  Cldn4; claudin-4 [KO:K06087]
306454  Cldn22; claudin-22 [KO:K06087]
315953  Cldn18; claudin-18 precursor [KO:K06087]
65129  Cldn1; claudin-1 [KO:K06087]
65130  Cldn3; claudin-3 [KO:K06087]
65131  Cldn5; claudin-5 [KO:K06087]
84588  Cldn11; claudin-11 [KO:K06087]
100361422  Cldn34c4; claudin 34C4 [KO:K06087]
155268  Cldn16; claudin-16 [KO:K06087]
287098  Cldn6; claudin-6 precursor [KO:K06087]
287099  Cldn9; claudin-9 [KO:K06087]
680178  Cldn20; claudin-20 precursor [KO:K06087]
65132  Cldn7; claudin-7 precursor [KO:K06087]
680489  Cldn34e; uncharacterized protein LOC680489 [KO:K06087]
680370  Cldn34d; claudin 34D [KO:K06087]
502083  Cldn24; putative claudin-24 [KO:K06087]
100360390  Cldn25; putative claudin-25 [KO:K06087]
500000  Cldn12; claudin-12 [KO:K06087]
83497  Ocln; occludin [KO:K06088]
300519  Esam; endothelial cell-selective adhesion molecule precursor [KO:K06787]
25361  Vcam1; vascular cell adhesion protein 1 precursor [KO:K06527]
54319  Ezr; ezrin [KO:K08007]
81521  Msn; moesin [KO:K05763]
100361457  Actg1l1; actin, gamma 1 propeptide-like [KO:K05692]
81822  Actb; actin, cytoplasmic 1 [KO:K05692]
287876  Actg1; actin, cytoplasmic 2 [KO:K05692]
120098222  POTE ankyrin domain family member F [KO:K05692]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
363875  Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
66021  Cybb; cytochrome b-245 beta chain [KO:K21421] [EC:1.-.-.-]
79129  Cyba; cytochrome b-245 light chain [KO:K08009]
364018  Ncf2; neutrophil cytosol factor 2 [KO:K08010]
114553  Ncf1; neutrophil cytosolic factor 1 [KO:K08011]
500904  Ncf4; neutrophil cytosol factor 4 [KO:K08012]
84353  Ctnnb1; catenin beta-1 [KO:K02105]
311163  Ctnnd1; catenin delta-1 [KO:K05690]
307505  Ctnna1; catenin alpha-1 [KO:K05691]
297357  Ctnna2; catenin alpha-2 isoform 1 [KO:K05691]
361839  Ctnna3; catenin alpha-3 [KO:K05691]
25622  Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform 2 [KO:K07293] [EC:3.1.3.48]
81686  Mmp2; 72 kDa type IV collagenase precursor [KO:K01398] [EC:3.4.24.24]
81687  Mmp9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
25464  Icam1; intercellular adhesion molecule 1 precursor [KO:K06490]
25738  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
29337  Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
25614  Ptk2; focal adhesion kinase 1 [KO:K05725] [EC:2.7.10.2]
360820  Pxn; paxillin isoform 1 [KO:K05760]
25414  Bcar1; breast cancer anti-estrogen resistance protein 1 isoform 3 [KO:K05726]
24832  Thy1; thy-1 membrane glycoprotein preproprotein [KO:K06514]
306400  Arhgap35; rho GTPase-activating protein 35 [KO:K05732]
299012  Arhgap5; rho GTPase-activating protein 5 [KO:K13709]
117273  Rhoa; transforming protein RhoA [KO:K04513]
297173  RSA-14-44; ras homolog gene family, member A [KO:K04513]
81762  Rock1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.39]
25537  Rock2; rho-associated protein kinase 2 [KO:K17388] [EC:2.7.11.39]
363925  Myl2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
289759  Myl7; myosin regulatory light chain 2, atrial isoform [KO:K12754]
296313  Myl9; myosin regulatory light polypeptide 9 [KO:K12755]
501831  Myl10; myosin regulatory light chain 10 [KO:K12756]
501203  Myl12a; myosin regulatory light chain RLC-A [KO:K12757]
50685  Myl12b; myosin regulatory light chain 12B [KO:K12757]
24584  Myl11; myosin regulatory light chain 11 [KO:K12758]
26955  Afdn; afadin [KO:K05702]
295347  Rap1a; ras-related protein Rap-1A [KO:K04353]
171337  Rap1b; ras-related protein Rap-1b precursor [KO:K07836]
361710  Sipa1; signal-induced proliferation-associated protein 1 [KO:K08013]
361517  Vasp; vasodilator-stimulated phosphoprotein [KO:K06274]
63836  Actn4; alpha-actinin-4 [KO:K05699]
81634  Actn1; alpha-actinin-1 [KO:K05699]
305679  Vcl; vinculin [KO:K05700]
24772  Cxcl12; stromal cell-derived factor 1 isoform beta precursor [KO:K10031]
60628  Cxcr4; C-X-C chemokine receptor type 4 [KO:K04189]
25686  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
25643  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
81664  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
59326  Rapgef3; rap guanine nucleotide exchange factor 3 [KO:K08014]
252857  Rapgef4; rap guanine nucleotide exchange factor 4 [KO:K04351]
54355  Rassf5; ras association domain-containing protein 5 [KO:K08015]
50646  Ptk2b; protein-tyrosine kinase 2-beta [KO:K05871] [EC:2.7.10.2]
363577  Itk; tyrosine-protein kinase ITK/TSK [KO:K07363] [EC:2.7.10.2]
305311  Txk; tyrosine-protein kinase TXK [KO:K08016] [EC:2.7.10.2]
25156  Vav1; proto-oncogene vav [KO:K05730]
295378  Vav3; guanine nucleotide exchange factor VAV3 [KO:K05730]
296603  Vav2; guanine nucleotide exchange factor VAV2 [KO:K05730]
366957  Rac2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
64465  Cdc42; cell division control protein 42 homolog [KO:K04393]
305341  Rhoh; rho-related GTP-binding protein RhoH [KO:K07873]
Compound
C00027  Hydrogen peroxide
C00076  Calcium cation
C00575  3',5'-Cyclic AMP
C04637  1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate
Reference
PMID:14976004
  Authors
van Buul JD, Hordijk PL.
  Title
Signaling in leukocyte transendothelial migration.
  Journal
Arterioscler Thromb Vasc Biol 24:824-33 (2004)
DOI:10.1161/01.ATV.0000122854.76267.5c
Reference
PMID:15604886
  Authors
Wittchen ES, van Buul JD, Burridge K, Worthylake RA.
  Title
Trading spaces: Rap, Rac, and Rho as architects of transendothelial migration.
  Journal
Curr Opin Hematol 12:14-21 (2005)
DOI:10.1097/01.moh.0000147892.83713.a7
Reference
PMID:14977592
  Authors
Barreiro O, Vicente-Manzanares M, Urzainqui A, Yanez-Mo M, Sanchez-Madrid F.
  Title
Interactive protrusive structures during leukocyte adhesion and transendothelial migration.
  Journal
Front Biosci 9:1849-63 (2004)
DOI:10.2741/1285
Reference
PMID:15629883
  Authors
Cook-Mills JM, Deem TL.
  Title
Active participation of endothelial cells in inflammation.
  Journal
J Leukoc Biol 77:487-95 (2005)
DOI:10.1189/jlb.0904554
Reference
PMID:15173832
  Authors
Imhof BA, Aurrand-Lions M.
  Title
Adhesion mechanisms regulating the migration of monocytes.
  Journal
Nat Rev Immunol 4:432-44 (2004)
DOI:10.1038/nri1375
Reference
PMID:15265790
  Authors
Deem TL, Cook-Mills JM.
  Title
Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species.
  Journal
Blood 104:2385-93 (2004)
DOI:10.1182/blood-2004-02-0665
Reference
PMID:10975856
  Authors
Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO.
  Title
ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines.
  Journal
J Immunol 165:3375-83 (2000)
DOI:10.4049/jimmunol.165.6.3375
Reference
PMID:12540948
  Authors
Chavakis T, Preissner KT, Santoso S.
  Title
Leukocyte trans-endothelial migration: JAMs add new pieces to the puzzle.
  Journal
Thromb Haemost 89:13-7 (2003)
DOI:10.1055/s-0037-1613537
Reference
PMID:15771581
  Authors
Berg LJ, Finkelstein LD, Lucas JA, Schwartzberg PL.
  Title
Tec family kinases in T lymphocyte development and function.
  Journal
Annu Rev Immunol 23:549-600 (2005)
DOI:10.1146/annurev.immunol.22.012703.104743
Related
pathway
rno04514  Cell adhesion molecules
rno04810  Regulation of actin cytoskeleton
KO pathway
ko04670   
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