A Novel and Critical Role for Tyrosine 663 in Platelet Endothelial Cell Adhesion Molecule-1 Trafficking and Transendothelial Migration

Dasgupta, B.; Dufour, Éric; Mamdouh, Zahra; Müller, William A.

doi:10.4049/jimmunol.0803192

Cited by 52 publications

(62 citation statements)

References 31 publications

(59 reference statements)

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“…2 Platelet/endothelial cell adhesion molecule 1 (PECAM-1) expressed in the EC plasma membrane is also critically involved in the mechanism of PMN transmigration. 5,6 Based on the key roles of both ICAM-1 and PECAM-1, a fundamental question is whether these adhesive proteins cooperate in the mechanism of PMN transmigration.…”

Section: Introductionmentioning

confidence: 99%

ICAM-1–activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration

Liu¹,

Place²,

Chen³

et al. 2012

Blood

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Polymorphonuclear neutrophil (PMN) extravasation requires selectin-mediated tethering, intercellular adhesion molecule-1 (ICAM-1)–dependent firm adhesion, and platelet/endothelial cell adhesion molecule 1 (PECAM-1)–mediated transendothelial migration. An important unanswered question is whether ICAM-1–activated signaling contributes to PMN transmigration mediated by PECAM-1. We tested this concept and the roles of endothelial nitric oxide synthase (eNOS) and Src activated by PMN ligation of ICAM-1 in mediating PECAM-1–dependent PMN transmigration. We observed that lung PMN infiltration in vivo induced in carrageenan-injected WT mice was significantly reduced in ICAM-1−/− and eNOS−/− mice. Crosslinking WT mouse ICAM-1 expressed in human endothelial cells (ECs), but not the phospho-defective Tyr518Phe ICAM-1 mutant, induced SHP-2–dependent Src Tyr530 dephosphorylation that resulted in Src activation. ICAM-1 activation also stimulated phosphorylation of Akt (p-Ser473) and eNOS (p-Ser1177), thereby increasing NO production. PMN migration across EC monolayers was abolished in cells expressing the Tyr518Phe ICAM-1 mutant or by pretreatment with either the Src inhibitor PP2 or eNOS inhibitor L-NAME. Importantly, phospho–ICAM-1 induction of Src signaling induced PECAM-1 Tyr686 phosphorylation and increased EC surface anti–PECAM-1 mAb-binding activity. These results collectively show that ICAM-1–activated Src and eNOS signaling sequentially induce PECAM-1–mediated PMN transendothelial migration. Both Src and eNOS inhibition may be important therapeutic targets to prevent or limit vascular inflammation.

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Section: Introductionmentioning

confidence: 99%

ICAM-1–activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration

Liu¹,

Place²,

Chen³

et al. 2012

Blood

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“…Alternatively, signaling mediated by PECAM-1 cytoplasmic ITIMs has been suggested to have a role in maintaining the vascular barrier because PECAM-1 expression has been reported to modulate -catenin phosphorylation and enhance vascular barrier stability through ITIM-mediated recruitment of SHP-2 (Biswas et al, 2006). Two other groups, however, found that ITIM-mediated recruitment of SHP-2 by endothelial cell PECAM-1 is not required for leukocyte transmigration through cell monolayers (Dasgupta et al, 2009;O'Brien et al, 2003), a process that involves the coordinated opening and closing of cell-cell junctions, which is very similar to the process occurring during regulation of vascular permeability. Finally, a role for raft-localized PECAM-1 is suggested by a report that PECAM-1 modulates signaling from the sphingosine-1-phosphate (S1P) receptor (Gratzinger et al, 2003) -a G-proteincoupled receptor that promotes barrier protection by enhancing junctional assembly via signaling in lipid rafts (Komarova et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity

Privratsky

Paddock

Florey

et al. 2011

Journal of Cell Science

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SummaryPECAM-1 (CD31) is a cellular adhesion and signaling receptor that is highly expressed at endothelial cell-cell junctions in confluent vascular beds. Previous studies have implicated PECAM-1 in the maintenance of vascular barrier integrity; however, the mechanisms behind PECAM-1-mediated barrier protection are still poorly understood. The goal of the present study, therefore, was to examine the pertinent biological properties of PECAM-1 (i.e. adhesion and/or signaling) that allow it to support barrier integrity. We found that, compared with PECAM-1-deficient endothelial cells, PECAM-1-expressing endothelial cell monolayers exhibit increased steady-state barrier function, as well as more rapid restoration of barrier integrity following thrombin-induced perturbation of the endothelial cell monolayer. The majority of PECAM-1-mediated barrier protection was found to be due to the ability of PECAM-1 to interact homophilically and become localized to cell-cell junctions, because a homophilic binding-crippled mutant form of PECAM-1 was unable to support efficient barrier function when re-expressed in cells. By contrast, cells expressing PECAM-1 variants lacking residues known to be involved in PECAM-1-mediated signal transduction exhibited normal to near-normal barrier integrity. Taken together, these studies suggest that PECAM-1-PECAM-1 homophilic interactions are more important than its signaling function for maintaining the integrity of endothelial cell junctions.

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“…Differences in the rate at which membrane proteins transit through the LBRC could also potentially affect their distribution on the surface versus LBRC. In a previous study, we showed that substitution of phenylalanine for tyrosine at position 663 in the cytoplasmic tail of PECAM decreases the efficiency of trafficking of PECAM into and out of the LBRC (and hence of targeted recycling required for leukocyte transmigration), but does not totally eliminate it (Dasgupta et al, 2009). During the constitutive recycling assays performed in our previous study, endothelial cells were exposed to antibody for 1 hour, which was sufficient time to saturate native PECAM, but might not have been enough time for a slowly recycling mutant.…”

Section: Discussionmentioning

confidence: 94%

“…We hoped that understanding how PECAM entered the LBRC would provide clues to how other components enter. Previous studies have demonstrated that mutation of tyrosine 663 in the PECAM cytoplasmic tail to phenylalanine interferes with the efficient movement of PECAM between the endothelial cell border and the LBRC (Dasgupta et al, 2009). However, standard signaling functions of PECAM were not altered (Dasgupta et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have demonstrated that mutation of tyrosine 663 in the PECAM cytoplasmic tail to phenylalanine interferes with the efficient movement of PECAM between the endothelial cell border and the LBRC (Dasgupta et al, 2009). However, standard signaling functions of PECAM were not altered (Dasgupta et al, 2009). This suggests the possibility that, similar to some other cytoplasmic tail tyrosine motifs (Lipardi et al, 2002;Rohrer et al, 1996), there is a recognition signal on the cytoplasmic tail of PECAM for inclusion into the LBRC.…”

Section: Introductionmentioning

confidence: 99%

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Segregation of VE-cadherin from the LBRC depends on the ectodomain sequence required for homophilic adhesion

Feng

Sullivan

Han

et al. 2014

Journal of Cell Science

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The lateral border recycling compartment (LBRC) is a reticulum of perijunctional tubulovesicular membrane that is continuous with the plasmalemma of endothelial cells and is essential for efficient transendothelial migration (TEM) of leukocytes. The LBRC contains molecules involved in TEM, such as PECAM, PVR and CD99, but not VE-cadherin. Despite its importance, how membrane proteins are included in or excluded from the LBRC is not known. Immunoelectron microscopy and biochemical approaches demonstrate that inclusion into the LBRC is the default pathway for transmembrane molecules present at endothelial cell borders. A chimeric molecule composed of the extracellular domain of VEcadherin and cytoplasmic tail of PECAM (VE-CAD/PECAM) did not enter the LBRC, suggesting that VE-cadherin was excluded by a mechanism involving its extracellular domain. Deletion of the homophilic interaction domain EC1 or the homophilic interaction motif RVDAE allowed VE-CAD/PECAM and even native VEcadherin to enter the LBRC. Similarly, treatment with RVDAE peptide to block homophilic VE-cadherin interactions allowed endogenous VE-cadherin to enter the LBRC. This suggests that homophilic interactions of VE-cadherin stabilize it at cell borders and prevent entry into the LBRC.

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A Novel and Critical Role for Tyrosine 663 in Platelet Endothelial Cell Adhesion Molecule-1 Trafficking and Transendothelial Migration

Cited by 52 publications

References 31 publications

ICAM-1–activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration

ICAM-1–activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration

Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity

Segregation of VE-cadherin from the LBRC depends on the ectodomain sequence required for homophilic adhesion

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