KEGG   PATHWAY: pcad04670
Entry
pcad04670                   Pathway                                
Name
Leukocyte transendothelial migration - Physeter catodon (sperm whale)
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
pcad04670  Leukocyte transendothelial migration
pcad04670

Other DBs
GO: 0050900
Organism
Physeter catodon (sperm whale) [GN:pcad]
Gene
102984634  JAM3; junctional adhesion molecule C isoform X1 [KO:K06785]
102987095  integrin alpha-M [KO:K06461]
102983789  ITGB2; integrin beta-2 [KO:K06464]
102977114  JAM2; junctional adhesion molecule B isoform X1 [KO:K06735]
102977938  ITGA4; integrin alpha-4 [KO:K06483]
102984702  ITGB1; integrin beta-1 isoform X2 [KO:K05719]
102980906  PECAM1; platelet endothelial cell adhesion molecule isoform X1 [KO:K06471]
112062072  CD99; CD99 antigen isoform X1 [KO:K06520]
102991384  XG; glycoprotein Xg isoform X2 [KO:K06520]
102989919  CD99L2; CD99 antigen-like protein 2 isoform X7 [KO:K06520]
102973622  integrin alpha-L [KO:K05718]
102973290  F11R; junctional adhesion molecule A [KO:K06089]
102986838  cadherin-5 [KO:K06533]
102976666  CLDN12; claudin-12 [KO:K06087]
102991039  CLDN5; claudin-5 [KO:K06087]
102996273  CLDN17; claudin-17 [KO:K06087]
102996547  CLDN8; claudin-8 [KO:K06087]
102995168  CLDN18; claudin-18 isoform X1 [KO:K06087]
102980304  CLDN7; claudin-7 [KO:K06087]
102990015  CLDN2; claudin-2 [KO:K06087]
102978984  CLDN3; claudin-3 [KO:K06087]
102979254  CLDN4; claudin-4 [KO:K06087]
102973122  CLDN6; claudin-6 [KO:K06087]
102973404  CLDN9; claudin-9 [KO:K06087]
112064622  CLDN20; claudin-20 [KO:K06087]
102983012  CLDN11; claudin-11 [KO:K06087]
102977631  CLDN19; claudin-19 [KO:K06087]
112066929  CLDN23; claudin-23 [KO:K06087]
102974905  CLDN25; putative claudin-25 [KO:K06087]
102982454  CLDN10; claudin-10 isoform X1 [KO:K06087]
102993298  CLDN15; claudin-15 isoform X3 [KO:K06087]
102983686  LOW QUALITY PROTEIN: claudin-22 [KO:K06087]
102983193  putative claudin-24 [KO:K06087]
102982489  CLDN14; claudin-14 [KO:K06087]
102993458  CLDN1; claudin-1 [KO:K06087]
102994006  CLDN16; claudin-16 [KO:K06087]
102986179  OCLN; occludin isoform X1 [KO:K06088]
102979528  ESAM; endothelial cell-selective adhesion molecule [KO:K06787]
102996805  VCAM1; vascular cell adhesion protein 1 [KO:K06527]
102979086  LOW QUALITY PROTEIN: vascular cell adhesion protein 1-like [KO:K06527]
102992810  EZR; LOW QUALITY PROTEIN: ezrin [KO:K08007]
102994837  MSN; moesin isoform X2 [KO:K05763]
102988048  ACTG1; actin, cytoplasmic 2 [KO:K05692]
102988905  actin, cytoplasmic 1 [KO:K05692]
112063645  actin, cytoplasmic 1 isoform X2 [KO:K05692]
102986098  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102978952  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102977108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102975555  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102991779  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102991192  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102979195  rho-related BTB domain-containing protein 2 [KO:K04392]
102990276  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X2 [KO:K04392]
102993493  cytochrome b-245 heavy chain [KO:K21421] [EC:1.-.-.-]
102973615  cytochrome b-245 light chain [KO:K08009]
102987030  NCF2; neutrophil cytosol factor 2 isoform X1 [KO:K08010]
102982542  NCF1; neutrophil cytosol factor 1 isoform X2 [KO:K08011]
102993692  NCF4; neutrophil cytosol factor 4 [KO:K08012]
102987227  CTNNB1; catenin beta-1 [KO:K02105]
102978519  CTNND1; catenin delta-1 isoform X1 [KO:K05690]
102980163  CTNNA1; catenin alpha-1 [KO:K05691]
102973482  CTNNA2; catenin alpha-2 [KO:K05691]
102995753  CTNNA3; catenin alpha-3 isoform X3 [KO:K05691]
102979922  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:3.1.3.48]
102987506  tyrosine-protein phosphatase non-receptor type 11-like isoform X1 [KO:K07293] [EC:3.1.3.48]
102973920  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
102977941  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
102977531  MAPK12; mitogen-activated protein kinase 12 isoform X3 [KO:K04441] [EC:2.7.11.24]
102989111  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
102990302  MAPK13; mitogen-activated protein kinase 13 isoform X3 [KO:K04441] [EC:2.7.11.24]
102977994  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
102988478  ICAM1; intercellular adhesion molecule 1 [KO:K06490]
102992700  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
102983230  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
102974888  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
102974383  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
102983841  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
102982229  PTK2; focal adhesion kinase 1 isoform X1 [KO:K05725] [EC:2.7.10.2]
102975066  PXN; paxillin isoform X2 [KO:K05760]
102974736  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X3 [KO:K05726]
102995429  THY1; thy-1 membrane glycoprotein [KO:K06514]
102991062  ARHGAP35; rho GTPase-activating protein 35 [KO:K05732]
102980106  ARHGAP5; rho GTPase-activating protein 5 [KO:K13709]
102983639  RHOA; transforming protein RhoA [KO:K04513]
102987332  ROCK1; rho-associated protein kinase 1 [KO:K04514] [EC:2.7.11.1]
102994518  ROCK2; rho-associated protein kinase 2 isoform X2 [KO:K17388] [EC:2.7.11.1]
102983557  MYL2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
102985354  MYL5; myosin light chain 5 [KO:K12753]
102975231  MYL7; myosin regulatory light chain 2, atrial isoform [KO:K12754]
102985793  MYL9; myosin regulatory light polypeptide 9 [KO:K12755]
102973456  MYL10; myosin regulatory light chain 10 [KO:K12756]
102993300  myosin regulatory light polypeptide 9 isoform X1 [KO:K12757]
102993761  myosin regulatory light chain 12B [KO:K12757]
102996446  MYL11; myosin regulatory light chain 11 [KO:K12758]
102990362  AFDN; afadin isoform X6 [KO:K05702]
102985661  RAP1A; ras-related protein Rap-1A isoform X1 [KO:K04353]
102980344  RAP1B; ras-related protein Rap-1b [KO:K07836]
102989853  LOW QUALITY PROTEIN: ras-related protein Rap-1b-like [KO:K07836]
102987967  SIPA1; signal-induced proliferation-associated protein 1 isoform X2 [KO:K08013]
102982276  VASP; vasodilator-stimulated phosphoprotein isoform X1 [KO:K06274]
102973544  ACTN1; alpha-actinin-1 isoform X2 [KO:K05699]
102994912  ACTN4; alpha-actinin-4 isoform X1 [KO:K05699]
102983025  VCL; vinculin isoform X2 [KO:K05700]
102990097  CXCL12; stromal cell-derived factor 1 [KO:K10031]
102989559  CXCR4; C-X-C chemokine receptor type 4 [KO:K04189]
102996618  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
102997009  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
102996666  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
102987186  rap guanine nucleotide exchange factor 3 isoform X2 [KO:K08014]
102985646  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X2 [KO:K04351]
102995774  RASSF5; ras association domain-containing protein 5 [KO:K08015]
102995810  PTK2B; protein-tyrosine kinase 2-beta isoform X1 [KO:K05871] [EC:2.7.10.2]
102994407  ITK; tyrosine-protein kinase ITK/TSK [KO:K07363] [EC:2.7.10.2]
102993111  TXK; tyrosine-protein kinase TXK [KO:K08016] [EC:2.7.10.2]
102976346  VAV1; proto-oncogene vav [KO:K05730]
102973743  VAV2; guanine nucleotide exchange factor VAV2 [KO:K05730]
102988564  VAV3; guanine nucleotide exchange factor VAV3 [KO:K05730]
102990552  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
102975958  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
102994723  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
pcad04514  Cell adhesion molecules
pcad04810  Regulation of actin cytoskeleton
KO pathway
ko04670   
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