KEGG PATHWAY: hsa04670

PATHWAY: hsa04670

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

Pathway map

hsa04670

Leukocyte transendothelial migration

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

Drug

D02404	Procaterol hydrochloride (USAN)
D02811	Alicaforsen sodium (USAN)
D03061	Batimastat (USAN/INN)
D03959	Efalizumab (USAN/INN)
D04000	Enlimomab (USAN/INN)
D06886	Natalizumab (INN)
D08993	Rovelizumab (USAN/INN)
D10028	Valategrast hydrochloride (USAN)

Other DBs

BSID:

83083

GO:

0050900

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]
100132463	CLDN24; claudin 24 [KO:K06087]
100506658	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:K04514] [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

PMID:14976004

Authors

van Buul JD, Hordijk PL.

Title

Signaling in leukocyte transendothelial migration.

Journal

Arterioscler Thromb Vasc Biol 24:824-33 (2004)

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)

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)

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)

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)

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)

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)

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)

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)

KO pathway

ko04670

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Ontology (3)   
   KEGG BRITE (3)   
Pathway (1)   
   BioSystems (1)   
Disease (6)   
   KEGG DISEASE (6)   
Drug (8)   
   KEGG DRUG (8)   
Genome (1)   
   KEGG GENOME (1)   
Gene (118)   
   KEGG GENES (118)   
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