Entry 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 systemBRITE hierarchy
Pathway map hsa04670 Leukocyte transendothelial migration
Drug D02811 Alicaforsen sodium (USAN)
D05029 Midostaurin (JAN/USAN/INN)
D09799 Carotegrast methyl (JAN)
D10028 Valategrast hydrochloride (USAN)
D10392 Lifitegrast sodium (USAN)
D10463 Ripasudil hydrochloride hydrate (JAN/USAN)
D11527 Zolbetuximab (USAN/INN)
D12799 Vociprotafib (USAN/INN)
D12892 Migoprotafib (USAN/INN)
Other DBs Organism Homo sapiens (human) [GN:
hsa ]
Gene 10411 RAPGEF3; Rap guanine nucleotide exchange factor 3 [KO:K08014 ]
10451 VAV3; vav guanine nucleotide exchange factor 3 [KO:K05730 ]
11069 RAPGEF4; Rap guanine nucleotide exchange factor 4 [KO:K04351 ]
1535 CYBA; cytochrome b-245 alpha chain [KO:K08009 ]
1536 CYBB; cytochrome b-245 beta chain [KO:K21421 ] [EC:1.-.-.-]
2770 GNAI1; G protein subunit alpha i1 [KO:K04630 ]
2771 GNAI2; G protein subunit alpha i2 [KO:K04630 ]
2773 GNAI3; G protein subunit alpha i3 [KO:K04630 ]
2909 ARHGAP35; Rho GTPase activating protein 35 [KO:K05732 ]
3383 ICAM1; intercellular adhesion molecule 1 [KO:K06490 ]
387 RHOA; ras homolog family member A [KO:K04513 ]
394 ARHGAP5; Rho GTPase activating protein 5 [KO:K13709 ]
399 RHOH; ras homolog family member H [KO:K07873 ]
4267 CD99; CD99 molecule (Xg blood group) [KO:K06520 ]
4301 AFDN; afadin, adherens junction formation factor [KO:K05702 ]
4688 NCF2; neutrophil cytosolic factor 2 [KO:K08010 ]
4689 NCF4; neutrophil cytosolic factor 4 [KO:K08012 ]
5175 PECAM1; platelet and endothelial cell adhesion molecule 1 [KO:K06471 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [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 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
5906 RAP1A; RAP1A, member of RAS oncogene family [KO:K04353 ]
5908 RAP1B; RAP1B, member of RAS oncogene family [KO:K07836 ]
6093 ROCK1; Rho associated coiled-coil containing protein kinase 1 [KO:K04514 ] [EC:2.7.11.1 ]
6387 CXCL12; C-X-C motif chemokine ligand 12 [KO:K10031 ]
6494 SIPA1; signal-induced proliferation-associated 1 [KO:K08013 ]
7408 VASP; vasodilator stimulated phosphoprotein [KO:K06274 ]
7409 VAV1; vav guanine nucleotide exchange factor 1 [KO:K05730 ]
7410 VAV2; vav guanine nucleotide exchange factor 2 [KO:K05730 ]
7412 VCAM1; vascular cell adhesion molecule 1 [KO:K06527 ]
7852 CXCR4; C-X-C motif chemokine receptor 4 [KO:K04189 ]
83593 RASSF5; Ras association domain family member 5 [KO:K08015 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
90952 ESAM; endothelial cell adhesion molecule [KO:K06787 ]
9475 ROCK2; Rho associated coiled-coil containing protein kinase 2 [KO:K17388 ] [EC:2.7.11.1 ]
9564 BCAR1; BCAR1 scaffold protein, Cas family member [KO:K05726 ]
998 CDC42; cell division cycle 42 [KO:K04393 ]
Compound C04637 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate
Reference Authors van Buul JD, Hordijk PL.
Title Signaling in leukocyte transendothelial migration.
Journal Reference Authors Wittchen ES, van Buul JD, Burridge K, Worthylake RA.
Title Trading spaces: Rap, Rac, and Rho as architects of transendothelial migration.
Journal 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 Reference Authors Cook-Mills JM, Deem TL.
Title Active participation of endothelial cells in inflammation.
Journal Reference Authors Imhof BA, Aurrand-Lions M.
Title Adhesion mechanisms regulating the migration of monocytes.
Journal 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 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 Reference Authors Chavakis T, Preissner KT, Santoso S.
Title Leukocyte trans-endothelial migration: JAMs add new pieces to the puzzle.
Journal Reference Authors Berg LJ, Finkelstein LD, Lucas JA, Schwartzberg PL.
Title Tec family kinases in T lymphocyte development and function.
Journal Related hsa04810 Regulation of actin cytoskeleton
KO pathway
