Leukocyte transendothelial migration - Homo sapiens (human)

Curator(s): Joe Strothman

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.    
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Leukocyte transendothelial migration - Homo sapiens (human) cluster_Endothelium Endothelium cluster_node34 Endothelium membrane 2 cluster_node35 Endothelium membrane 2DS cluster_node36 Endothelium membrane 1 cluster_node37 Leukocyte membrane 2 cluster_node38 !tm cluster_node39 Leukocyte Membrane 1 cluster_Leukocyte Leukocyte node5 6 node7 3 PECAM1 2 node7->PECAM1 2 node9 6 node10 8 node12 5 JAM1 node12->JAM1 node13 6 integrin,alpha 4 (antigen CD49D,alpha 4 subunit of VLA-4 receptor) ITGA4 node13->ITGA4 ITGB1 2 node13->ITGB1 2 node14 7 integrin,alpha M (complement component 3 receptor 3 subunit) ITGAM node14->ITGAM integrin,beta 2 (complement component 3 receptor 3 and 4 subunit) ITGB2 node14->ITGB2 node16 12 node19 5 node22 5 node25 4 node28 4 node32 2 node1 1 node2 2 node1->node2 CAMs 2 node2->CAMs 2 CAMs 2A node2->CAMs 2A node30 10 FAK node30->FAK Paxillin node30->Paxillin pl30Cas node30->pl30Cas node20 Beta-caterin PECAM1 2->node20 node8 4 CDH5 2 node8->CDH5 2 node23 Beta-caterin 2 CDH5 2->node23 pl20ctn CDH5 2->pl20ctn node17 AF-6 Rap1 node17->Rap1 RHOA 2 Rap1->RHOA 2 Actin 1 Docking structure 1 Actin 1->Docking structure 1 node24 Alpha-Caterin Actin node24->Actin node20->node19 Beta-caterin node23->node22 Beta-caterin 2 node23->node24 CAMs 1 CAMs 1->node1 CAMs 1A CAMs 1A->node1 CD99 1 CD99 2 CD99 1->CD99 2 cell division cycle 42 (GTP binding protein,25kDa) CDC42 Direction sensing CDC42->Direction sensing ras-related C3 botulinum toxin substrate 1 (rho family,small GTP binding protein Rac1) RAC1 CDC42->RAC1 CDH5 1 CDH5 1->node8 chemokine (C-X-C motif) receptor 4 CXCR4 Pyk2 CXCR4->Pyk2 node11 SDF-1 CXCR4->node11 Vav 2 Pyk2->Vav 2 node33 CYBA NCF2 NCF1 NCF4 H2O2 node33->H2O2 MMPs H2O2->MMPs node21 SHP-2 H2O2->node21 node29 SHP-2 2 H2O2->node29 p38 H2O2->p38 node26 Ca2+ node26->Docking structure 1 node26->node33 Nox node26->Nox Nox->H2O2 node27 Ca2+ 2 node27->Docking structure 1 PKC 2 node27->PKC 2 PKC 2->node28 PKC 2 PKC 2->node30 node31 Stress-fibers contraction PKC 2->node31 EPAC node15 RAPL~Rap1 EPAC->node15 node4 ITGA4 ITGB1 node15->node4 node6 ITGAL ITGB2 node15->node6 node3 ITGAM ITGB2 node15->node3 ERM 1 ERM 1->Actin 1 ERM 2 ERM 2->Actin 1 Gi Gi->CXCR4 PI3K Gi->PI3K cAMP Gi->cAMP PI3K->node16 PI3K tec protein tyrosine kinase TEC PI3K->TEC cAMP->EPAC MMPs->node5 MMPs Transendothelial migration MMPs->Transendothelial migration node21->Transendothelial migration node29->node7 p38->node32 p38 p38->node29 ? p38->node31 ? intercellular adhesion molecule 1 ICAM1 ICAM1->node10 ICAM1 ICAM1->ERM 2 PLCgamma ICAM1->PLCgamma ICAM1->RHOA 2 PLCgamma->node27 RHOA 2->node30 ROCK 2 RHOA 2->ROCK 2 vascular cell adhesion molecule 1 VCAM1 node4->VCAM1 VCAM1->node9 VCAM1 VCAM1->node26 VCAM1->ERM 1 PI3K 2 VCAM1->PI3K 2 integrin,alpha L (antigen CD11A (p180),lymphocyte function-associated antigen 1; alpha polypeptide) ITGAL ITGAL->node12 node6->Pyk2 node6->ICAM1 VAV node6->VAV ras homolog gene family,member A RHOA VAV->RHOA Thy-1 cell surface antigen THY1 node3->THY1 RhoGAP THY1->RhoGAP integrin,beta 1 (fibronectin receptor,beta polypeptide,antigen CD29 includes MDF2,MSK12) ITGB1 ITGB1->node12 junctional adhesion molecule 2 JAM2 JAM2->node13 JAM3 1 JAM3 1->node14 MLC Tail retraction MLC->Tail retraction MLC 2 MLC 2->Actin PECAM1 1 PECAM1 1->node7 TEC->Vav 2 +p PI3K 2->node25 PI3K 2 Rac1 2 PI3K 2->Rac1 2 Rac1 2->Docking structure 1 Rac1 2->node33 Rac1 2->Nox Vav 2->CDC42 ras-related C3 botulinum toxin substrate 2 (rho family,small GTP binding protein Rac2) RAC2 Vav 2->RAC2 Cell motility RAC2->Cell motility ROCK RHOA->ROCK ROCK->MLC +p ROCK 2->MLC 2 +p ras homolog gene family,member H RHOH RHOH->node6 RhoGAP->RHOA 2 node18 SPA-1 node18->Rap1 print "