IQGAP1 Mediates VE-Cadherin–Based Cell–Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis

Yamaoka‐Tojo, Minako; Tojo, Taiki; Kim, Ha Won; Hilenski, Lula; Patrushev, Nikolay; Zhang, Lynn; Fukai, Tohru; Ushio‐Fukai, Masuko

doi:10.1161/01.atv.0000231524.14873.e7

Cited by 105 publications

(94 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IQGAP1 has been shown to colocalize with AJ cadherin complex and regulate cadherin-mediated cell-cell adhesion [24,26,27]. In EC, we observed IQGAP1 enrichment at the interendothelial junctions (Fig.…”

Section: Iqgap1 Is Localized To Interendothelial Junctionsmentioning

confidence: 57%

“…IQGAP1 has been implicated to participate in dynamic interendothelial junction remodeling after VEGF stimulation [27]. IQGAP1 couples VEGFR2 to the b-catenin/VE-cadherin complex to facilitate VEGF-stimulated events such as tyrosine phosphorylation of VE-cadherin.…”

Section: Discussionmentioning

confidence: 99%

“…IQGAP1 interacts with actin by a calponin homology domain [20], indirectly with microtubules (MT) through interaction with CLIP-170, a MT-Plus-End-Tracking-protein [21][22][23], and localizes to the adherens junction (AJ) cadherin complex by its c-terminus domain [24][25][26][27]. IQGAP1 integrates Ca 21 /calmodulin with Rho GTP-binding protein signaling at spatially restricted areas of the cell [26,28].…”

Section: Introductionmentioning

confidence: 99%

“…IQGAP1 integrates Ca 21 /calmodulin with Rho GTP-binding protein signaling at spatially restricted areas of the cell [26,28]. Functionally, recent work implicates IQGAP1 in remodeling of VE-cadherin-dependent interendothelial contacts during vascular endothelial growth factor (VEGF) stimulated angiogenesis [27].MT regulate the intercellular AJ in EC. A population of MT extend to AJ and are involved in concentrating E-cadherin at the intercellular junction [29].…”

mentioning

confidence: 99%

“…These interventions promote accumulation of lymphocytes on the luminal surface of the EC monolayer, above the level of VE-cadherin. Surprisingly, a similar fraction of such lymphocytes were associated with an underlying gap in the VE-cadherin band among IQGAP1 knockdown, MT depolymerization, and control monolayers.IQGAP1 has been implicated to participate in dynamic interendothelial junction remodeling after VEGF stimulation [27]. IQGAP1 couples VEGFR2 to the b-catenin/VE-cadherin complex to facilitate VEGF-stimulated events such as tyrosine phosphorylation of VE-cadherin.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

2009

View full text Add to dashboard Cite

Leukocyte movement from the blood to the tissues is a fundamental process in acute and chronic inflammatory diseases. While the role of endothelial cells (EC) to recruit leukocytes to sites of inflammation is well known, the mechanisms that control remodeling of EC shape and adhesive contacts during leukocyte transendothelial migration (TEM) are not completely understood. We studied the role of IQGAP1, an adaptor protein that binds to filamentous-actin and microtubules (MT) at interendothelial junctions, during lymphocyte TEM. EC IQGAP1 knockdown decreases MT tethered to the adherens junction, and decreases lymphocyte TEM to $70% (po0.05) versus control. Similarly, loss of adherens junction-associated MT induced by brief nocodazole (ND) treatment decreases lymphocyte TEM to $65% of control (po0.01). Confocal microscopy imaging indicates that EC IQGAP1 knockdown and MT depolymerization both result in lymphocyte accumulation above the vascular endothelial cadherin (VE-cadherin) junctions and reduces the fraction of adherent lymphocytes that complete diapedesis across interendothelial cell junctions. However, we observe no change in VE-cadherin gap formation underlying adherent lymphocytes among control, IQGAP1 knockdown, or MT depolymerised EC monolayers. These data indicate that IQGAP1 contributes to MT stability at endothelial junctions. Further, IQGAP1 is involved in junction remodeling required for efficient lymphocyte diapedesis, independent of VE-cadherin gap formation.Key words: Adherens junctions . Cytoskeleton . IQGAP1 Supporting Information available online IntroductionLeukocyte extravasation is fundamental to the development of many immune responses including solid-organ allograft rejection. In this process, leukocytes leave the bloodstream and migrate into tissues through the endothelial cells (EC) that line the walls of vessels, i.e. leukocytes undergo transendothelial migration (TEM). Whereas the specific adhesion molecules, chemoattractants, and possibly signaling pathways involved in TEM are unique among different subgroups of leukocytes and vascular beds, the interaction between leukocytes and EC during TEM can be generalized into a multicascade event, described in recent reviews [1][2][3]. EC and leukocyte adhesion molecules mediate tethering and rolling of leukocytes on EC followed by chemokinemediated leukocyte activation, then firm adhesion to the EC. Finally, adherent leukocytes crawl on the surface of endothelium, undergo diapedesis, and enter tissues by mechanisms that are not fully understood.Leukocyte transmigration may occur by either a transcellular, through EC, or paracellular route, between adjacent EC [4][5][6]. 204The latter is associated with structural changes in the interendothelial adhesion structures and EC cytoskeleton [5,7,8]. Cross-linking of adhesion molecules such as CD54 or CD106 is shown to mediate signals that lead to EC actin cytoskeleton remodeling [9][10][11][12]. These signaling cascades promote structural changes in interendothlelial junctions, which might be requ...

show abstract

Section: Iqgap1 Is Localized To Interendothelial Junctionsmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

2009

View full text Add to dashboard Cite

show abstract

Signaling To and Through The Endothelial Adherens Junction

Ferreri

Vincent

2008

Cell Junctions

View full text Add to dashboard Cite

IQGAP1 involvement in MTOC and granule polarization in NK‐cell cytotoxicity

Kanwar

Wilkins

2011

Eur J Immunol

View full text Add to dashboard Cite

Natural killer (NK) cells form a region of tight contact called the NK immunological synapse (NKIS) with their target cells. This is a dynamic region serving as a platform for targeted signaling and exocytotic events. We previously identified IQGAP1 as a cytoskeletal component of the NK-like cell line YTS. The present study was undertaken to determine the role of IQGAP1 in the function of NK cells. Silencing of IQGAP1 expression resulted in almost complete loss of the cytotoxic activity of YTS cells. Loss of IQGAP1 did not prevent conjugate formation with target cells but it did result in a failure to reorient the microtubule organizing centre to the immune synapse. Significantly, IQGAP1 expression was required for the perigranular accumulation of an F-actin network. IQGAP1 was shown to undergo marked rearrangements during synapse maturation in effector target conjugates of YTS or primary NK cells. These results suggest previously undescribed role(s) for IQGAP1 in regulating multiple aspects of cytoskeletal organization and granule polarization in NK cells.Key words: Immune synapse . IQGAP1 . MTOC . NK cells . shRNA Supporting Information available online IntroductionNatural killer (NK) cells are lymphocytes of the innate immune system that eliminate allogeneic cells and cells undergoing physiological stress due to viral, bacterial, or parasitic infection or malignant transformation [1][2][3][4][5]. NK cells form an immunological synapse (NKIS) that serves to tether them to target cells and provide a site for the targeted delivery of lytic granules [6,7]. In order to achieve this, a series of coordinated surface and intracellular molecular changes must occur within the NK cells [8]. These include the polarization and patterning of surface proteins, formation of a submembranous actin matrix, and the reorientation of the microtubule organizing centre (MTOC) for the delivery and fusion of granules with the effector membrane. Once some of the granules have fused with the plasma membrane, the NK cells disengage from their targets to repeat this process with other target cells.These processes of target cell engagement and degranulation are carefully regulated involving a coordinated sequence of events. These include extensive reorganization of NKIS surface elements to form specialized regions for membrane granule fusion [9]. Concurrently, the actin and tubulin cytoskeleton and associated molecules reorganize to allow granules access to the membrane [10,11]. While many of the membrane proximal events involved in NKIS formation have been characterized, the composition of the more distal NKIS elements has not been fully Eur. J. Immunol. 2011. 41: 2763-2773 DOI 10.1002 Molecular immunology 2763 determined, in part because of the difficulties associated with the isolation of these structures. In an effort to define the NKIS composition, we previously performed a proteomic analysis of the cytoskeletal elements of an NK-like cell line YTS, with subsequent structural and bioinformatic approaches to identify candidate synapse...

show abstract

IQGAP1 Mediates VE-Cadherin–Based Cell–Cell Contacts and VEGF Signaling at Adherence Junctions Linked to Angiogenesis

Cited by 105 publications

References 29 publications

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

Signaling To and Through The Endothelial Adherens Junction

IQGAP1 involvement in MTOC and granule polarization in NK‐cell cytotoxicity

Contact Info

Product

Resources

About