A mechanism of Rap1-induced stabilization of endothelial cell–cell junctions

Liu, Jian J.; Stockton, Rebecca; Gingras, Alexandre R.; Ablooglu, Ararat J.; Han, Jaewon; Bobkov, Andrey A.; Ginsberg, Mark H.

doi:10.1091/mbc.e11-02-0157

Cited by 59 publications

(115 citation statements)

References 43 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…Previous reports show that several negatively charged residues [aspartate (D) and glutamate (E)] in Rap1 mediate its interaction with the RBD domain of RalGDS, a known Rap1-binding protein ( Fig. 3A) (Liu et al, 2011). As such, we mutated these negatively charged residues in Rap1 to alanine (i.e.…”

Section: Identification Of Rap1 As An Interacting Partner Of Gaba B Rmentioning

confidence: 99%

GABAB receptor promotes its own surface expression by recruiting a Rap1-dependent signaling cascade

Zhang

Huang

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

G-protein-coupled receptors (GPCRs) are key players in cell signaling, and their cell surface expression is tightly regulated. For many GPCRs such as β2-AR (β2-adrenergic receptor), receptor activation leads to downregulation of receptor surface expression, a phenomenon that has been extensively characterized. By contrast, some other GPCRs, such as GABA B receptor, remain relatively stable at the cell surface even after prolonged agonist treatment; however, the underlying mechanisms are unclear. Here, we identify the small GTPase Rap1 as a key regulator for promoting GABA B receptor surface expression. Agonist stimulation of GABA B receptor signals through Gαi/o to inhibit Rap1GAPII (also known as Rap1GAP1b, an isoform of Rap1GAP1), thereby activating Rap1 (which has two isoforms, Rap1a and Rap1b) in cultured cerebellar granule neurons (CGNs). The active form of Rap1 is then recruited to GABA B receptor through physical interactions in CGNs. This Rap1-dependent signaling cascade promotes GABA B receptor surface expression by stimulating receptor recycling. Our results uncover a new mechanism regulating GPCR surface expression and also provide a potential explanation for the slow, long-lasting inhibitory action of GABA neurotransmitter.

show abstract

Section: Identification Of Rap1 As An Interacting Partner Of Gaba B Rmentioning

confidence: 99%

GABAB receptor promotes its own surface expression by recruiting a Rap1-dependent signaling cascade

Zhang

Huang

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Recent crystallographic analysis revealed a novel mode of interaction between the KRIT1 FERM domain and the small GTPase Rap1 that represents a paradigm for how small G-proteins can bind and recognize FERM domains (Gingras et al, 2013;Li et al, 2012). Rap1 binding inhibits the binding of KRIT1 to microtubules (Béraud-Dufour et al, 2007), thereby enabling the relocalization of KRIT1 and the stabilization of cell-cell junctions (Liu et al, 2011). The molecular mechanisms by which this occurs are not yet known, but KRIT1 binds Rap1 and microtubules through different domains, suggesting that there is a conformational regulation controlling the subcellular localization of KRIT1 (discussed below).…”

Section: Ccm Proteins Krit1mentioning

confidence: 99%

“…The KRIT1 FERM domain can also bind to the membrane anchor protein heart of glass 1 (HEG1), a protein essential for KRIT1 junction localization. The functional importance of these interactions is highlighted in zebrafish studies, as KRIT1 mutants that are unable to bind either Rap1 or HEG1 do not rescue the KRIT1-null (santa) phenotype, which is associated with defects in cardiovascular development (Gingras et al, 2012;Liu et al, 2011) (see supplementary material Table S1). …”

Section: Ccm Proteins Krit1mentioning

confidence: 99%

Cerebral cavernous malformation proteins at a glance

Draheim

Fisher

Boggon

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 (also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs). These abnormalities are characterized by dilated leaky blood vessels, especially in the neurovasculature, that result in increased risk of stroke, focal neurological defects and seizures. The three CCM proteins can exist in a trimeric complex, and each of these essential multi-domain adaptor proteins also interacts with a range of signaling, cytoskeletal and adaptor proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, migration, polarity and apoptosis. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of current models of CCM protein function focusing on how known protein-protein interactions might contribute to cellular phenotypes and highlighting gaps in our current understanding.

show abstract

“…KRIT1 displays a domain structure with several potential protein binding sites (30,31). Although KRIT1 interaction with activated Rap1 is critical for the basal maintenance of endothelial junctional integrity (32), molecular inhibition of KRIT1 increases basal Rho activation (33). These functional properties suggest KRIT1 as a bona fide Rap1 effector with signaling functions at cell adhesions essential for regulation of EC vascular barrier in basal conditions and upon stimulation with injurious stimuli.…”

Section: Clinical Relevancementioning

confidence: 99%

Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6

Meliton

Meng

Tian

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Mechanisms of vascular endothelial cell (EC) barrier regulation during acute lung injury (ALI) or other pathologies associated with increased vascular leakiness are an active area of research. Adaptor protein krev interaction trapped-1 (KRIT1) participates in angiogenesis, lumen formation, and stabilization of EC adherens junctions (AJs) in mature vasculature. We tested a role of KRIT1 in the regulation of Rho-GTPase signaling induced by mechanical stimulation and barrier dysfunction relevant to ventilator-induced lung injury and investigated KRIT1 involvement in EC barrier protection by prostacyclin (PC). PC stimulated Ras-related protein 1 (Rap1)-dependent association of KRIT1 with vascular endothelial cadherin at AJs, with KRIT1-dependent cortical cytoskeletal remodeling leading to EC barrier enhancement. KRIT1 knockdown exacerbated Rho-GTPase activation and EC barrier disruption induced by pathologic 18% cyclic stretch and thrombin receptor activating peptide (TRAP) 6 and attenuated the protective effects of PC. In the two-hit model of ALI caused by high tidal volume (HTV) mechanical ventilation and TRAP6 injection, KRIT1 functional deficiency in KRIT1 1/2 mice increased basal lung vascular leak and augmented vascular leak and lung injury caused by exposure to HTV and TRAP6. Down-regulation of KRIT1 also diminished the protective effects of PC against TRAP6/HTV-induced lung injury. These results demonstrate a KRIT1-dependent mechanism of vascular EC barrier control in basal conditions and in the two-hit model of ALI caused by excessive mechanical forces and TRAP6 via negative regulation of Rho activity and enhancement of cell junctions. We also conclude that the stimulation of the Rap1-KRIT1 signaling module is a major mechanism of vascular endothelial barrier protection by PC in the injured lung.

show abstract

A mechanism of Rap1-induced stabilization of endothelial cell–cell junctions

Abstract: Rap1 stabilizes cell–cell junctions by directly binding to KRIT1, displacing it from microtubules and enabling localization at the junctions.

Cited by 59 publications

References 43 publications

GABAB receptor promotes its own surface expression by recruiting a Rap1-dependent signaling cascade

GABAB receptor promotes its own surface expression by recruiting a Rap1-dependent signaling cascade

Cerebral cavernous malformation proteins at a glance

Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6

Contact Info

Product

Resources

About