Angiopoietin-2 Stimulation of Endothelial Cells Induces αvβ3 Integrin Internalization and Degradation

Thomas, Markus; Felcht, Moritz; Kruse, Karoline; Kretschmer, Stella; Deppermann, Carleen; Biesdorf, Andreas; Rohr, Karl; Benest, Andrew V.; Fiedler, Ulrike; Augustin, Hellmut G.

doi:10.1074/jbc.m109.097543

Cited by 89 publications

(85 citation statements)

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“…Confirming previous studies on the non-cytotoxicity of the ANG-2 antibody (26), treatment did not impair cell survival (Supplemental Figure 6F), necrosis (Supplemental Figure 6H), or apoptosis (Supplemental Figure 6G). These findings suggest that the protective effect of ANG-2 on ECs is mediated in an intracellular autocrine manner, as has previously been inferred from cellular experiments (13,14).…”

Section: Ang-2 Induces Ec Migration In Tie2 Losupporting

confidence: 82%

“…In contrast to the destabilizing roles of ANG-2 on resting ECs (13,14), ANG-2 has been shown to act as an antiapoptotic protective factor for stressed ECs (15), which themselves are particularly strong producers of ANG-2 (16,17). Several groups have recently reported that the ANG-2-positive tumor endothelium harbors a subpopulation of ECs that do not express its receptor TIE2 (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

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Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

et al. 2012

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Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2 lo ). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2 lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2 lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling.

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Section: Ang-2 Induces Ec Migration In Tie2 Losupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

et al. 2012

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“…Recent reports have shown that the integrin degradation pathway is also essential for the control of cell behavior [5,44]. Association between cells and the extracellular matrix is effectively regulated by the integrin degradation pathway [7]. The key finding in this study is that exosomes act as an inducer of the integrin degradation pathway.…”

Section: Discussionmentioning

confidence: 63%

“…Ubiquitination of integrin acts as a signal to trigger trafficking of internalized integrin to the lysosomal degradation compartment [5,6]. The degradation process is important for controlling the proper expression level of integrin on the cell surface, by which cell-matrix association and cell migration are tightly regulated [5,7].Integrin is a key regulator of cellular functions associated with vascular processes [8,9]. Endothelial cell migration and leukocyte recruitment during inflammation are tightly controlled by integrin functions.…”

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confidence: 99%

Exosomes derived from human macrophages suppress endothelial cell migration by controlling integrin trafficking

Lee

Kim

2014

Eur J Immunol

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Integrin trafficking, including internalization, recycling, and lysosomal degradation, is crucial for the regulation of cellular functions. Exosomes, nano-sized extracellular vesicles, are believed to play important roles in intercellular communications. This study demonstrates that exosomes released from human macrophages negatively regulate endothelial cell migration through control of integrin trafficking. Macrophage-derived exosomes promote internalization of integrin β1 in primary HUVECs. The internalized integrin β1 persistently accumulates in the perinuclear region and is not recycled back to the plasma membrane. Experimental results indicate that macrophage-derived exosomes stimulate trafficking of internalized integrin β1 to lysosomal compartments with a corresponding decrease in the integrin destined for recycling endosomes, resulting in proteolytic degradation of the integrin. Moreover, ubiquitination of HUVEC integrin β1 is enhanced by the exosomes, and exosome-mediated integrin degradation is blocked by bafilomycin A, a lysosomal degradation inhibitor. Macrophage-derived exosomes were also shown to effectively suppress collagen-induced activation of the mitogenactivated protein kinase/extracellular signal-regulated kinase signaling pathway and HUVEC migration, which are both dependent on integrin β1. These observations provide new insight into the functional significance of exosomes in the regulation of integrin trafficking. Keywords: Endothelial cell migration r Exosomes r Integrin trafficking r MacrophagesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIntegrin, a heterodimeric transmembrane receptor composed of α-and β-subunits, has a fundamental role in communication between cells and the extracellular matrix [1,2]. Recent studies have shown that trafficking of integrin is a crucial step in this communication [3][4][5]. Integrin is regularly internalized via the endocytosis pathway and internalized integrin is recycled back to the plasma membrane [3,4]. Internalized integrin β1, the most widely expressed integrin subunit, accumulates in the perinuclear Correspondence: Dr. Doo-Sik Kim e-mail: dskim@yonsei.ac.kr region of cells and is returned to the plasma membrane through RAB11-positive recycling endosomes [3]. The recycling process rearranges the distribution of integrins on the cell surface and controls the direction of cell migration [3]. Ubiquitination of integrin acts as a signal to trigger trafficking of internalized integrin to the lysosomal degradation compartment [5,6]. The degradation process is important for controlling the proper expression level of integrin on the cell surface, by which cell-matrix association and cell migration are tightly regulated [5,7].Integrin is a key regulator of cellular functions associated with vascular processes [8,9]. Endothelial cell migration and leukocyte recruitment during inflammation are tightly controlled by integrin functions. The expression and activation of integrins C...

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“…Furthermore, overexpression of Ang2 in MCF-7 promoted their metastasis to lymph nodes and lungs, an effect postulated to result from direct interaction between Ang2 and beta1 integrins on tumor cells (much the way Ang2 was reported to facilitate sprouting of Tie2-negative tip cells; refs. 11,27). The delineation of autocrine versus paracrine presentation of Ang2 still needs to be carefully investigated.…”

Section: Outstanding Questions and Future Directions For Rational Intmentioning

confidence: 99%

Angiopoietin-2: An Attractive Target for Improved Antiangiogenic Tumor Therapy

Gerald¹,

Chintharlapalli²,

Augustin³

et al. 2013

Cancer Research

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167

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Anti-VEGF pathway therapies primarily target immature blood vessels in tumors. However, emerging approaches to combine with targeted therapies impacting the later stages of remodeling and vessel maturation are expected to improve clinical efficacy by expanding the target vessel population. The angiopoietin/Tie ligand/ receptor system is a prototypic regulator of vessel remodeling and maturation. Angiopoietin-2 (Ang2) appears to be a particularly attractive therapeutic target. In fact, the experimental proof-of-concept showing improved efficacy when VEGF and Ang2-targeting therapies are combined has been solidly established in preclinical models, and several Ang2-targeting drugs are in clinical trials. However, rational development of these secondgeneration combination therapies is hampered by a limited understanding of the biological complexity that is generated from agonistic and antagonistic Ang/Tie signaling. This review discusses recent mechanistic advances in angiopoietin signaling, particularly in light of the recent study published on REGN910 and summarizes the status quo of Ang2-targeting therapies. In light of the clarified partial agonist function of Ang2, we propose that clarity on the expression profile of the angiopoietin ligands and Tie1 and Tie2 receptors in subsets of cancer vessels and cancer cells will provide clearer hypotheses for more focused rational clinical trials to exploit this seminal pathway and improve current antiangiogenic therapies. Cancer Res; 73(6); 1649-57. Ó2013 AACR.

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Angiopoietin-2 Stimulation of Endothelial Cells Induces αvβ3 Integrin Internalization and Degradation

Cited by 89 publications

References 44 publications

Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

Exosomes derived from human macrophages suppress endothelial cell migration by controlling integrin trafficking

Angiopoietin-2: An Attractive Target for Improved Antiangiogenic Tumor Therapy

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