KEGG   PATHWAY: hsa04670Help
Entry
hsa04670                    Pathway                                

Name
Leukocyte transendothelial migration - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Leukocyte transendothelial migration
hsa04670

All organismsOrtholog table
Disease
H00099  
Leukocyte adhesion deficiency (LAD)
H00742  
Neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome
H00840  
Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG)
H00947  
Pilomatricoma
H01018  
Metachondromatosis
H01255  
Juvenile-onset dystonia
H01387  
Activated PI3K-delta syndrome (APDS)
Drug
D02811  
Alicaforsen sodium (USAN)
D03061  
Batimastat (USAN/INN)
D03959  
Efalizumab (USAN/INN)
D04000  
Enlimomab (USAN/INN)
D06886  
Natalizumab (genetical recombination) (JAN)
D08993  
Rovelizumab (USAN/INN)
D10028  
Valategrast hydrochloride (USAN)
Other DBs
BSID: 
GO: 
Organism
Homo sapiens (human) [GN:hsa]
Gene
83700  
JAM3; junctional adhesion molecule 3 [KO:K06785]
3684  
ITGAM; integrin, alpha M (complement component 3 receptor 3 subunit) [KO:K06461]
3689  
ITGB2; integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) [KO:K06464]
58494  
JAM2; junctional adhesion molecule 2 [KO:K06735]
3676  
ITGA4; integrin, alpha 4 (antigen CD49D, alpha 4 subunit of VLA-4 receptor) [KO:K06483]
3688  
ITGB1; integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) [KO:K05719]
5175  
PECAM1; platelet/endothelial cell adhesion molecule 1 [KO:K06471]
4267  
CD99; CD99 molecule [KO:K06520]
3683  
ITGAL; integrin, alpha L (antigen CD11A (p180), lymphocyte function-associated antigen 1 [KO:K05718]
50848  
F11R; F11 receptor [KO:K06089]
1003  
CDH5; cadherin 5, type 2 (vascular endothelium) [KO:K06533]
1364  
CLDN4; claudin 4 [KO:K06087]
1365  
CLDN3; claudin 3 [KO:K06087]
1366  
CLDN7; claudin 7 [KO:K06087]
149461  
CLDN19; claudin 19 [KO:K06087]
10686  
CLDN16; claudin 16 [KO:K06087]
23562  
CLDN14; claudin 14 [KO:K06087]
24146  
CLDN15; claudin 15 [KO:K06087]
26285  
CLDN17; claudin 17 [KO:K06087]
49861  
CLDN20; claudin 20 [KO:K06087]
5010  
CLDN11; claudin 11 [KO:K06087]
51208  
CLDN18; claudin 18 [KO:K06087]
53842  
CLDN22; claudin 22 [KO:K06087]
7122  
CLDN5; claudin 5 [KO:K06087]
9071  
CLDN10; claudin 10 [KO:K06087]
9073  
CLDN8; claudin 8 [KO:K06087]
9074  
CLDN6; claudin 6 [KO:K06087]
9075  
CLDN2; claudin 2 [KO:K06087]
9076  
CLDN1; claudin 1 [KO:K06087]
9080  
CLDN9; claudin 9 [KO:K06087]
137075  
CLDN23; claudin 23 [KO:K06087]
644672  
CLDN25; claudin 25 [KO:K06087]
CLDN24; claudin 24 [KO:K06087]
OCLN; occludin [KO:K06088]
90952  
ESAM; endothelial cell adhesion molecule [KO:K06787]
7412  
VCAM1; vascular cell adhesion molecule 1 [KO:K06527]
7430  
EZR; ezrin [KO:K08007]
4478  
MSN; moesin [KO:K05763]
60  
ACTB; actin, beta [KO:K05692]
71  
ACTG1; actin, gamma 1 [KO:K05692]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase, regulatory subunit 1 (alpha) [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase, regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase, regulatory subunit 2 (beta) [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase, regulatory subunit 3 (gamma) [KO:K02649]
5879  
RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
50508  
NOX3; NADPH oxidase 3 [KO:K08008]
27035  
NOX1; NADPH oxidase 1 [KO:K08008]
1536  
CYBB; cytochrome b-245, beta polypeptide [KO:K08008]
1535  
CYBA; cytochrome b-245, alpha polypeptide [KO:K08009]
4688  
NCF2; neutrophil cytosolic factor 2 [KO:K08010]
653361  
NCF1; neutrophil cytosolic factor 1 [KO:K08011]
4689  
NCF4; neutrophil cytosolic factor 4, 40kDa [KO:K08012]
1499  
CTNNB1; catenin (cadherin-associated protein), beta 1, 88kDa [KO:K02105]
1500  
CTNND1; catenin (cadherin-associated protein), delta 1 [KO:K05690]
29119  
CTNNA3; catenin (cadherin-associated protein), alpha 3 [KO:K05691]
1495  
CTNNA1; catenin (cadherin-associated protein), alpha 1, 102kDa [KO:K05691]
1496  
CTNNA2; catenin (cadherin-associated protein), alpha 2 [KO:K05691]
5781  
PTPN11; protein tyrosine phosphatase, non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
4313  
MMP2; matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase) [KO:K01398] [EC:3.4.24.24]
4318  
MMP9; matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) [KO:K01403] [EC:3.4.24.35]
5600  
MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  
MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  
MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  
MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
3383  
ICAM1; intercellular adhesion molecule 1 [KO:K06490]
5335  
PLCG1; phospholipase C, gamma 1 [KO:K01116] [EC:3.1.4.11]
5336  
PLCG2; phospholipase C, gamma 2 (phosphatidylinositol-specific) [KO:K05859] [EC:3.1.4.11]
5578  
PRKCA; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
5579  
PRKCB; protein kinase C, beta [KO:K02677] [EC:2.7.11.13]
5582  
PRKCG; protein kinase C, gamma [KO:K02677] [EC:2.7.11.13]
5747  
PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
5829  
PXN; paxillin [KO:K05760]
9564  
BCAR1; breast cancer anti-estrogen resistance 1 [KO:K05726]
7070  
THY1; Thy-1 cell surface antigen [KO:K06514]
2909  
ARHGAP35; Rho GTPase activating protein 35 [KO:K05732]
394  
ARHGAP5; Rho GTPase activating protein 5 [KO:K13709]
387  
RHOA; ras homolog family member A [KO:K04513]
6093  
ROCK1; Rho-associated, coiled-coil containing protein kinase 1 [KO:K04514] [EC:2.7.11.1]
9475  
ROCK2; Rho-associated, coiled-coil containing protein kinase 2 [KO:K17388] [EC:2.7.11.1]
4633  
MYL2; myosin, light chain 2, regulatory, cardiac, slow [KO:K10351]
4636  
MYL5; myosin, light chain 5, regulatory [KO:K12753]
58498  
MYL7; myosin, light chain 7, regulatory [KO:K12754]
10398  
MYL9; myosin, light chain 9, regulatory [KO:K12755]
93408  
MYL10; myosin, light chain 10, regulatory [KO:K12756]
103910  
MYL12B; myosin, light chain 12B, regulatory [KO:K12757]
10627  
MYL12A; myosin, light chain 12A, regulatory, non-sarcomeric [KO:K12757]
29895  
MYLPF; myosin light chain, phosphorylatable, fast skeletal muscle [KO:K12758]
4301  
MLLT4; myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) [KO:K05702]
5906  
RAP1A; RAP1A, member of RAS oncogene family [KO:K04353]
5908  
RAP1B; RAP1B, member of RAS oncogene family [KO:K07836]
6494  
SIPA1; signal-induced proliferation-associated 1 [KO:K08013]
7408  
VASP; vasodilator-stimulated phosphoprotein [KO:K06274]
87  
ACTN1; actinin, alpha 1 [KO:K05699]
88  
ACTN2; actinin, alpha 2 [KO:K05699]
89  
ACTN3; actinin, alpha 3 [KO:K05699]
81  
ACTN4; actinin, alpha 4 [KO:K05699]
7414  
VCL; vinculin [KO:K05700]
6387  
CXCL12; chemokine (C-X-C motif) ligand 12 [KO:K10031]
7852  
CXCR4; chemokine (C-X-C motif) receptor 4 [KO:K04189]
2770  
GNAI1; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1 [KO:K04630]
2773  
GNAI3; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 [KO:K04630]
2771  
GNAI2; guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2 [KO:K04630]
10411  
RAPGEF3; Rap guanine nucleotide exchange factor (GEF) 3 [KO:K08014]
11069  
RAPGEF4; Rap guanine nucleotide exchange factor (GEF) 4 [KO:K04351]
83593  
RASSF5; Ras association (RalGDS/AF-6) domain family member 5 [KO:K08015]
2185  
PTK2B; protein tyrosine kinase 2 beta [KO:K05871] [EC:2.7.10.2]
3702  
ITK; IL2-inducible T-cell kinase [KO:K07363] [EC:2.7.10.2]
7294  
TXK; TXK tyrosine kinase [KO:K08016] [EC:2.7.10.2]
10451  
VAV3; vav 3 guanine nucleotide exchange factor [KO:K05730]
7409  
VAV1; vav 1 guanine nucleotide exchange factor [KO:K05730]
7410  
VAV2; vav 2 guanine nucleotide exchange factor [KO:K05730]
5880  
RAC2; ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) [KO:K07860]
998  
CDC42; cell division cycle 42 [KO:K04393]
399  
RHOH; ras homolog family member H [KO:K07873]
Compound
C00027  
Hydrogen peroxide
C00076  
Calcium cation
C00575  
3',5'-Cyclic AMP
C04637  
1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate
Reference
  Authors
van Buul JD, Hordijk PL.
  Title
Signaling in leukocyte transendothelial migration.
  Journal
Arterioscler Thromb Vasc Biol 24:824-33 (2004)
Reference
  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)
Reference
  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)
Reference
  Authors
Cook-Mills JM, Deem TL.
  Title
Active participation of endothelial cells in inflammation.
  Journal
J Leukoc Biol 77:487-95 (2005)
Reference
  Authors
Imhof BA, Aurrand-Lions M.
  Title
Adhesion mechanisms regulating the migration of monocytes.
  Journal
Nat Rev Immunol 4:432-44 (2004)
Reference
  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)
Reference
  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)
Reference
  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)
Reference
  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)
KO pathway
 

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