Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity.
In this report, sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, is shown to activate tight-junction-associated protein Zonula Occludens-1 (ZO-1), which in turn plays a critical role in regulating endothelial chemotaxis and barrier integrity. After S1P stimulation, ZO-1 was redistributed to the lamellipodia and cell-cell junctions via the S1P1/G(i)/Akt/Rac pathway. Similarly, both endothelial barrier integrity and cell motility were significantly enhanced in S1P-treated cells through the G(i)/Akt/Rac pathway. Importantly, S1P-enhanced barrier integrity and cell migration were abrogated in ZO-1 knockdown cells, indicating ZO-1 is functionally indispensable for these processes. To investigate the underlying mechanisms, we demonstrated that cortactin plays a critical role in S1P-induced ZO-1 redistribution to the lamellipodia. In addition, S1P significantly induced the formation of endothelial tight junctions. ZO-1 and alpha-catenin polypeptides were colocalized in S1P-induced junctional structures; whereas, cortactin was not observed in these regions. Together, these results suggest that S1P induces the formation of two distinct ZO-1 complexes to regulate two different endothelial functions: ZO-1/cortactin complexes to regulate chemotactic response and ZO-1/alpha-catenin complexes to regulate endothelial barrier integrity. The concerted operation of these two ZO-1 complexes may coordinate two important S1P-mediated functions, i.e. migration and barrier integrity, in vascular endothelial cells.
Lee
Jen-Fu
JF
Gheens Center on Aging, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
Zeng
Qun
Q
Ozaki
Harunobu
H
Wang
Lichun
L
Hand
Arthur R
AR
Hla
Timothy
T
Wang
Eugenia
E
Lee
Menq-Jer
MJ
D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D051356:Cortactin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D010750:Phosphoproteins / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019108:Tight Junctions; D062826:Zonula Occludens-1 Protein
D051356:Cortactin; D008246:Lysophospholipids; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C060506:sphingosine 1-phosphate; D013110:Sphingosine