KEGG PATHWAY: ko04670

PATHWAY: ko04670

Entry

ko04670                     Pathway

Name

Leukocyte transendothelial migration

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

ko04670

Leukocyte transendothelial migration

Other DBs

GO:

0050900

Orthology

K00922

PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K01116

PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]

K01398

MMP2; matrix metalloproteinase-2 (gelatinase A) [EC:3.4.24.24]

K01403

MMP9; matrix metalloproteinase-9 (gelatinase B) [EC:3.4.24.35]

K02105

CTNNB1; catenin beta 1

K02649

PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K02677

PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]

K04189

CXCR4, CD184; C-X-C chemokine receptor type 4

K04351

RAPGEF4, EPAC2; Rap guanine nucleotide exchange factor 4

K04353

RAP1A; Ras-related protein Rap-1A

K04392

RAC1; Ras-related C3 botulinum toxin substrate 1

K04393

CDC42; cell division control protein 42

K04441

P38; p38 MAP kinase [EC:2.7.11.24]

K04513

RHOA; Ras homolog gene family, member A

K04514

ROCK1; Rho-associated protein kinase 1 [EC:2.7.11.39]

K04630

GNAI; guanine nucleotide-binding protein G(i) subunit alpha

K05690

CTNND1; catenin (cadherin-associated protein), delta 1

K05691

CTNNA; catenin alpha

K05692

ACTB_G1; actin beta/gamma 1

K05699

ACTN1_4; actinin alpha 1/4

K05700

VCL; vinculin

K05702

AF6, MLLT4; afadin

K05718

ITGAL, CD11a; integrin alpha L

K05719

ITGB1, CD29; integrin beta 1

K05725

PTK2, FAK; focal adhesion kinase 1 [EC:2.7.10.2]

K05726

BCAR1, CAS; breast cancer anti-estrogen resistance 1

K05730

VAV; guanine nucleotide exchange factor VAV

K05732

ARHGAP35, GRLF1; glucocorticoid receptor DNA-binding factor 1

K05760

PXN; paxillin

K05763

MSN; moesin

K05859

PLCG2; phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]

K05871

PTK2B, FAK2; focal adhesion kinase 2 [EC:2.7.10.2]

K06087

CLDN; claudin

K06088

OCLN; occludin

K06089

F11R, JAM1, CD321; junctional adhesion molecule 1

K06274

VASP; vasodilator-stimulated phosphoprotein

K06461

ITGAM, CD11b; integrin alpha M

K06464

ITGB2, CD18; integrin beta 2

K06471

PECAM1, CD31; platelet/endothelial cell adhesion molecule

K06483

ITGA4, CD49d; integrin alpha 4

K06490

ICAM1, CD54; intercellular adhesion molecule 1

K06514

THY1, CD90; Thy-1 cell surface antigen

K06520

CD99, MIC2; CD99 antigen

K06527

VCAM1, CD106; vascular cell adhesion molecule 1

K06533

CDH5, CD144; cadherin 5, type 2, VE-cadherin

K06735

JAM2, CD322; junctional adhesion molecule 2

K06785

JAM3; junctional adhesion molecule 3

K06787

ESAM; endothelial cell adhesion molecule

K07293

PTPN11, SHP2; tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48]

K07363

ITK; IL2-inducible T-cell kinase [EC:2.7.10.2]

K07836

RAP1B; Ras-related protein Rap-1B

K07860

RAC2; Ras-related C3 botulinum toxin substrate 2

K07873

RHOH, TTF; Ras homolog gene family, member H

K08007

EZR, VIL2; ezrin

K08009

CYBA, P22PHOX; cytochrome b-245, alpha polypeptide

K08010

NCF2, P67PHOX; neutrophil cytosolic factor 2

K08011

NCF1, P47PHOX; neutrophil cytosolic factor 1

K08012

NCF4, P40PHOX; neutrophil cytosolic factor 4

K08013

SIPA1; signal-induced proliferation-associated gene 1

K08014

RAPGEF3, EPAC1; Rap guanine nucleotide exchange factor 3

K08015

RASSF5, RAPL; Ras association domain-containing protein 5

K08016

TXK, RLK; tyrosine-protein kinase TXK [EC:2.7.10.2]

K10031

CXCL12; C-X-C motif chemokine 12

K10351

MYL2; myosin regulatory light chain 2

K12753

MYL5; myosin regulatory light chain 5

K12754

MYL7; myosin regulatory light chain 7

K12755

MYL9; myosin regulatory light chain 9

K12756

MYL10; myosin regulatory light chain 10

K12757

MYL12; myosin regulatory light chain 12

K12758

MYLPF; fast skeletal myosin light chain 2

K13709

ARHGAP5; Rho GTPase-activating protein 5

K17388

ROCK2; Rho-associated protein kinase 2 [EC:2.7.11.39]

K19662

PRKCB; classical protein kinase C beta type [EC:2.7.11.13]

K19663

PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]

K21421

NOX2, GP91, CYBB; NADPH oxidase 2 [EC:1.-.-.-]

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