VEGF Signals through ATF6 and PERK to Promote Endothelial Cell Survival and Angiogenesis in the Absence of ER Stress

Karali, Evdoxia; Bellou, Sofia; Stellas, Dimitris; Klinakis, Apostolos; Murphy, Carol; Fotsis, Theodore

doi:10.1016/j.molcel.2014.03.022

Cited by 159 publications

(148 citation statements)

References 49 publications

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“…It is tempting to speculate that macropinocytosis might be responsible for delivering signalling complexes of the receptor to downstream targets, such as ERK1/2 and Akt, that could reside at specific endosomal compartments (Dobrowolski and De Robertis, 2012;McKay and Morrison, 2007;Miaczynska et al, 2004;Platta and Stenmark, 2011;Schenck et al, 2008;Sorkin and von Zastrow, 2009;Teis et al, 2002;Zouggari et al, 2009). Consequently, macropinocytosis would link VEGFR2 to the downstream cascades required to regulate complex angiogenic responses, such as survival (Karali et al, 2014), proliferation and migration of endothelial cells (Herbert and Stainier, 2011).…”

Section: Discussionmentioning

confidence: 99%

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

Basagiannis

Zografou²,

Murphy

et al. 2016

Journal of Cell Science

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Endocytosis plays a crucial role in receptor signalling. VEGFR2 (also known as KDR) and its ligand VEGFA are fundamental in neovascularisation. However, our understanding of the role of endocytosis in VEGFR2 signalling remains limited. Despite the existence of diverse internalisation routes, the only known endocytic pathway for VEGFR2 is the clathrin-mediated pathway. Here, we show that this pathway is the predominant internalisation route for VEGFR2 only in the absence of ligand. Intriguingly, VEGFA induces a new internalisation itinerary for VEGFR2, the pathway of macropinocytosis, which becomes the prevalent endocytic route for the receptor in the presence of ligand, whereas the contribution of the clathrin-mediated route becomes minor. Macropinocytic internalisation of VEGFR2, which mechanistically is mediated through the small GTPase CDC42, takes place through macropinosomes generated at ruffling areas of the membrane. Interestingly, macropinocytosis plays a crucial role in VEGFAinduced signalling, endothelial cell functions in vitro and angiogenesis in vivo, whereas clathrin-mediated endocytosis is not essential for VEGFA signalling. These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA-driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis.

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Section: Discussionmentioning

confidence: 99%

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

Basagiannis

Zografou²,

Murphy

et al. 2016

Journal of Cell Science

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Section: Er Proteostasis Control In Glioma Stromal Cells Gliomas Reprmentioning

confidence: 99%

“…Upon binding to VEGFR on endothelial cells, VEGF activates the UPR sensors through the phospholipase Cg (PLCg) pathway without accumulation of misfolded proteins in the ER (59). This, in turn, promotes endothelial cell survival in an AKT-dependent manner and induces angiogenesis in mouse models (59). In addition, more recent work showing that signal transducer and activator of transcription 3 (STAT3)-or STAT6-activating cytokines yield predominantly IRE1-mediated cathepsin expression and secretion suggests that UPR activation in TAMs contributes to cancer invasion (125).…”

Section: Er Proteostasis Control In Glioma Stromal Cells Gliomas Reprmentioning

confidence: 99%

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

et al. 2017

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“…Genetic studies have demonstrated that PERK is essential in supporting tumor growth and progression via diverse mechanisms, including stimulation of angiogenesis (7)(8)(9)(10)(11)(12), potential effects on antitumor immunity (13,14), and direct increase in cancer cell viability by altering its metabolic status (15), promoting survival autophagy (16)(17)(18), and induction of prosurvival microRNAs (19). Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20,21).…”

mentioning

confidence: 99%

Type I interferons mediate pancreatic toxicities of PERK inhibition

Yu¹,

Zhao²,

Gui³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERKdeficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.T umor microenvironment-associated deficit in oxygen and nutrients activate numerous pathways that aid cancer and tumor stroma cells by increasing their ability to survive, withstand anticancer therapies, and ultimately select for more aggressive and viable clones capable of metastasizing (1). Activation of the unfolded protein response (UPR) plays a central role in these processes (2). Three branches of this response include stimulation of activating transcription factor-6 and activation of two kinases, inositol requiring enzyme 1α/β and the eukaryotic translation initiation factor 2-alpha kinase 3 [also termed double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, or pancreatic endoplasmic reticulum kinase (PERK)]. The latter kinase contributes to phosphorylation of the eukaryotic translation initiation factor 2-alpha and controls the rate of global translation and noncanonical induction of specific proteins that help cope with stress (reviewed in ref. 2).Among three main UPR pathways, signaling through PERK has received the most attention for its central role in cancer (3-6). Genetic studies have demonstrated that PERK is essential in supporting tumor growth and progression via diverse mechanisms, including stimulation of angiogenesis (7-12), potential effects on antitumor immunity (13,14), and direct increase in cancer cell viability by altering its metabolic status (15), promoting survival autophagy (16-18), and induction of prosurvival microRNAs (19). Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20, 21). Several PERK inhibitors have shown promising results in various preclinical tumor models (22-24). Furthermore, some of these inhibitors can protect against the prion-...

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VEGF Signals through ATF6 and PERK to Promote Endothelial Cell Survival and Angiogenesis in the Absence of ER Stress

Cited by 159 publications

References 49 publications

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

Type I interferons mediate pancreatic toxicities of PERK inhibition

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