TGFβ receptor internalization into EEA1-enriched early endosomes

Hayes, Stephen F; Chawla, Anil; Corvera, Silvia

doi:10.1083/jcb.200204088

Cited by 286 publications

(245 citation statements)

References 24 publications

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“…Previous studies have shown that TGF-β receptors undergo a rapid yet constant internalization in a ligand-dependent or -independent way [5][6][7][8][15][16][17]. The two major endocytic pathways, clathrin-mediated endocytosis and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-β receptors based on indirect evidence [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…One of the most important clathrin-independent pathways is mediated by caveolae, which are flask-shaped plasma membrane invaginations marked by the presence of caveolin-1 [1,4]. Understanding the mechanism of different endocytic pathways and how these pathways are regulated is of critical importance in the study of cell signaling process, especially for transforming growth factor-β (TGF-β) sig-npg www.cell-research.com | Cell Research naling, where TGF-β receptors harness both clathrin-and caveolae-dependent pathways for internalization [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…The two major endocytic pathways, clathrin-mediated endocytosis and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-β receptors based on indirect evidence [5][6][7][8]. For instance, TGF-β receptors were found to associate with clathrin-associated adaptor complex AP-2 or their endocytosis was dampened by potassium depletion, cytosol acidification or hypertonic buffer [6-8, 15, 18], and TGF-β receptors were observed to colocalize with caveolae at the plasma membrane or caveosomes in the cytoplasm [8,19,20].…”

Section: Introductionmentioning

confidence: 99%

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Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

Yan

et al. 2015

Cell Res

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Endocytosis and intracellular sorting of transforming growth factor-β (TGF-β) receptors play an important regulatory role in TGF-β signaling. Two major endocytic pathways, clathrin-and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-β receptors. In this study, we demonstrate that the clathrin-and caveolae-mediated endocytic pathways can converge during TGF-β receptor endocytic trafficking. By tracking the intracellular dynamics of fluorescently-labeled TGF-β type I receptor (TβRI), we found that after mediating TβRI internalization, certain clathrin-coated vesicles and caveolar vesicles are fused underneath the plasma membrane, forming a novel type of caveolin-1 and clathrin double-positive vesicles. Under the regulation of Rab5, the fused vesicles are targeted to early endosomes and thus deliver the internalized TβRI to the caveolin-1 and EEA1 double-positive early endosomes (caveolin-1-positive early endosomes). We further showed that the caveolin-1-positive early endosomes are positive for Smad3/SARA, Rab11 and Smad7/Smurf2, and may act as a multifunctional device for TGF-β signaling and TGF-β receptor recycling and degradation. Therefore, these findings uncover a novel scenario of endocytosis, the direct fusion of clathrin-coated and caveolae vesicles during TGF-β receptor endocytic trafficking, which leads to the formation of the multifunctional sorting device, caveolin-1-positive early endosomes, for TGF-β receptors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

Yan

et al. 2015

Cell Res

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“…In contrast to β 2 AR and EGFR, however, TGF-β type II receptor internalization is constitutive and independent of ligand binding [13]. The clathrin-dependent endocytosis of the TGF-β type II receptor is important for TGF-β-induced Smad activation and signaling transduction [14,15].…”

Section: Introductionmentioning

confidence: 99%

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

2008

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In eukaryotic cells, receptor endocytosis is a key event regulating signaling transduction. Adiponectin receptors belong to a new receptor family that is distinct from G-protein-coupled receptors and has critical roles in the pathogenesis of diabetes and metabolic syndrome. Here, we analyzed the endocytosis of adiponectin and adiponectin receptor 1 (AdipoR1) and found that they are both internalized into transferrin-positive compartments that follow similar traffic routes. Blocking clathrin-mediated endocytosis by expressing Eps15 mutants or depleting K + trapped AdipoR1 at the plasma membrane, and K + depletion abolished adiponectin internalization, indicating that the endocytosis of AdipoR1 and adiponectin is clathrin-dependent. Depletion of K + and overexpression of Eps15 mutants enhance adiponectinstimulated AMP-activated protein kinase phosphorylation, suggesting that the endocytosis of AdipoR1 might downregulate adiponectin signaling. In addition, AdipoR1 colocalizes with the small GTPase Rab5, and a dominant negative Rab5 abrogates AdipoR1 endocytosis. These data indicate that AdipoR1 is internalized through a clathrin-and Rab5-dependent pathway and that endocytosis may play a role in the regulation of adiponectin signaling.

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“…Internalization of activated RTK from plasma membrane is a critical step of signal transduction either by terminating membrane signaling or by redirecting and sustaining signaling intracellularly. Many studies, including a recent report on VEGFR-2, suggest that receptor signaling is maintained in the endosomal compartment, which may serve as a mechanism for sustaining and amplifying membrane signaling (Urbe et al, 2000;Hayes et al, 2002;Lampugnani et al, 2006). In this study, we investigated the contribution of internalized VEGFR-2 on intracellular signaling pathways leading to NO release.…”

mentioning

confidence: 99%

Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO Synthase

Duval

Bœuf

Huot

et al. 2007

MBoC

132

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Nitric oxide (NO) release from endothelial cells, via endothelial NO synthase (eNOS) activation, is central to the proangiogenic actions of vascular endothelial growth factor (VEGF). VEGF signaling to eNOS is principally mediated byan Akt-dependent phosphorylation of eNOS and by increased association of eNOS to the molecular chaperone, heatshock protein 90 kDa (Hsp90). Herein, we report that VEGFR-2 activation induces tyrosine phosphorylation of VEGF receptor 2 (VEGFR-2)-associated Hsp90␤. Tyrosine phosphorylation of Hsp90␤ in response to VEGF is dependent on internalization of the VEGFR-2 and on Src kinase activation. Furthermore, we demonstrate that c-Src directly phosphorylates Hsp90 on tyrosine 300 residue and that this event is essential for VEGF-stimulated eNOS association to Hsp90 and thus NO release from endothelial cells. Our work identifies Y300 phosphorylation of Hsp90 as a novel regulated posttranslational modification of the chaperone and demonstrates its importance in the proangiogenic actions of VEGF, namely by regulating NO release from endothelial cells. INTRODUCTIONVascular endothelial growth factor (VEGF) is a potent proangiogenic cytokine that activates three specific receptor tyrosine kinases (RTK): VEGF receptor (VEGFR)-1, -2, and -3. Gene knockout studies revealed that VEGF and VEGFRs are essential for the development of the vasculature in mouse embryos (Fong et al., 1995;Shalaby et al., 1995;Carmeliet et al., 1996;Dumont et al., 1998). In addition to its functional roles in vasculogenesis, VEGF plays key roles in adult physiological and pathological angiogenesis such as wound healing and tumor vascularization. VEGFR-2 mediates most of the functional and biochemical effects of VEGF in endothelial cells including proliferation, migration, survival, and nitric oxide (NO) release. These effects are produced through the activation of multiple signaling pathways, such as the phosphoinositide-3 kinase (PI-3 kinase)/ Akt, p38 mitogen-activated protein kinase (MAPK), phospholipase C (PLC)-␥, and Erk/MAPK, after the activation of VEGFR-2 (Rousseau et al., 1997;Takahashi and Shibuya, 1997;Gerber et al., 1998;Takahashi et al., 2001). VEGF-mediated activation of the Ser/Thr kinase Akt leads to phosphorylation of serine 1179 on bovine endothelial NO synthase (eNOS; Ser 1177 in the human form), which increases eNOS catalytic activity and results in release of NO from endothelial cells (Fulton et al., 1999;Dimmeler et al., 1999). In turn, NO released from endothelium contributes to the proangiogenic effects of VEGF. Indeed, VEGF-mediated vascular permeability, angiogenesis, and endothelial cell precursor mobilization are markedly impaired in eNOS-deficient mice (Fukumura et al., 2001;Aicher et al., 2003).Heat-shock protein 90 kDa (Hsp90) is a multifunctional molecular chaperone, and its role in the prevention of protein aggregation and in the refolding of denatured proteins has been studied in much detail (Whitesell and Lindquist, 2005). Hsp90 is also a regulator of the activity of signaling molecules su...

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TGFβ receptor internalization into EEA1-enriched early endosomes

Cited by 286 publications

References 24 publications

Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

Src-mediated Phosphorylation of Hsp90 in Response to Vascular Endothelial Growth Factor (VEGF) Is Required for VEGF Receptor-2 Signaling to Endothelial NO Synthase

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