Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes

Raiborg, Camilla; Bache, Kristi G.; Gillooly, David J.; Madshus, Inger Helene; Stang, Espen; Stenmark, Harald

doi:10.1038/ncb791

Cited by 646 publications

(710 citation statements)

References 30 publications

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“…This model for ubiquitinated cargo sorting into the MVB is similar to the one proposed for ubiquitin-dependent protein internalization in the endocytic pathway. The main difference is that the epsins required for endocytosis contain both the ENTH domain responsible for membrane deformations and the UIMs implicated in ubiquitinated receptor binding and in recruitment to the site of plasma membrane invaginations (Bilodeau et al, 2002;Polo et al, 2002;Raiborg et al, 2002;Shih et al, 2002). Here, in the case of the MVB pathway, a second effector, Vps27p, constitutes the link with ubiquinated cargo.…”

Section: Discussionmentioning

confidence: 99%

“…By binding to ubiquitinated cargo and then activating ESCRT-II, which in turn acts upstream of ESCRT-III, ESCRT-I is the first effector of a coordinated cascade necessary for ubiquitindependent protein sorting at the MVB (Babst et al, 2002a(Babst et al, , 2002b. Two other class E proteins, Vps27p and Hse1p, contain ubiquitin-interacting motifs (UIMs) and bind ubiquitin in vitro (Bilodeau et al, 2002;Polo et al, 2002;Raiborg et al, 2002;Shih et al, 2002). Mutations in the UIMs of Vps27p and Hse1p cause defects in sorting of Cps1p and Ste2p, suggesting that a Vps27p/Hse1p complex is a sorting receptor for ubiquitinated proteins at the MVB.…”

Section: Introductionmentioning

confidence: 99%

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Ent5p Is Required with Ent3p and Vps27p for Ubiquitin-dependent Protein Sorting into the Multivesicular Body

Eugster¹,

Pécheur²,

Michel

et al. 2004

MBoC

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At the late endosomes, cargoes destined for the interior of the vacuole are sorted into invaginating vesicles of the multivesicular body. Both PtdIns(3,5)P 2 and ubiquitin are necessary for proper sorting of some of these cargoes. We show that Ent5p, a yeast protein of the epsin family homologous to Ent3p, localizes to endosomes and specifically binds to PtdIns(3,5)P 2 via its ENTH domain. In cells lacking Ent3p and Ent5p, ubiquitin-dependent sorting of biosynthetic and endocytic cargo into the multivesicular body is disrupted, whereas other trafficking routes to the vacuole are not affected. Ent3p and Ent5p are associated with Vps27p, a FYVE domain containing protein that interacts with ubiquitinated cargoes and is required for protein sorting into the multivesicular body. Therefore, Ent3p and Ent5p are the first proteins shown to be connectors between PtdIns(3,5)P 2 -and the Vps27p-ubiquitin-driven sorting machinery at the multivesicular body. INTRODUCTIONEndosomes are crossroads between the biosynthetic and the endocytic pathways. Here, proteins destined for the lysosome/vacuole are segregated away from proteins recycling back to the plasma membrane or to the Golgi apparatus. A critical membrane segregation and protein-sorting event takes place in late endosomes, regions of endosomal membranes invaginate and vesicles bud into the lumen of the organelle, giving rise to the multivesicular body (MVB;Felder et al., 1990). Mature MVB fuses with the vacuole/ lysosome releasing internal vesicles into its lumen and thereby exposing them to the activity of hydrolytic enzymes (Futter et al., 1996;Odorizzi et al., 1998). This mechanism allows a subset of endosomal membrane proteins to be sorted to the lumen of the lysosome/vacuole, whereas others are either selectively recycled back to the Golgi or to the plasma membrane, or they end up on the lysosomal/vacuolar membrane (Pelham, 2002). In yeast, the MVB pathway is crucial for the regulated turnover of pheromone receptors and of some permeases (Odorizzi et al., 1998). Further, biosynthetic transmembrane proteins such as carboxypeptidase S (Cps1p) and Phm5p follow this route to reach their final destination, the vacuolar lumen (Odorizzi et al., 1998;Reggiori and Pelham, 2001;Epple et al., 2003).Ubiquitination has been implicated as an endosomal-sorting signal. Cps1p and Phm5p ubiquitination is essential to target them into the vacuolar lumen after sorting at the MVB (Katzmann et al., 2001;Reggiori and Pelham, 2001). Potential cargo receptors responsible for recognition and recruitment of ubiquitinated cargo into MVB vesicles are class E Vps (vacuolar protein sorting) proteins. Class E mutants accumulate cargo destined for the vacuole in an exaggerated endosomal structure and all (currently identified) class E proteins are required for sorting at the MVB (Conibear and Stevens, 1998). Vps23p, a class E protein of the ESCRT-I complex (endosomal-sorting complex required for transport), carries an ubiquitin-conjugating (UBC)-like domain and interacts directly with ubiquitin i...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ent5p Is Required with Ent3p and Vps27p for Ubiquitin-dependent Protein Sorting into the Multivesicular Body

Eugster¹,

Pécheur²,

Michel

et al. 2004

MBoC

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“…First, overexpression of Hrs causes the enlargement of early endosomes (Komada et al, 1997). Cell surface receptors such as EGFR and transferrin receptor, as well as other ubiquitinated proteins, are accumulated on these endosomes (Komada et al, 1997;Bishop et al, 2002;Raiborg et al, 2002;Morino et al, 2004). UBPY colocalized with overexpressed Hrs on the aberrant endosomes ( Figure 5).…”

Section: Subcellular Site Of Ubpy-mediated Egfr Deubiquitinationmentioning

confidence: 99%

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Mizuno

Iura

Mukai

et al. 2005

MBoC

249

262

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Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.

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“…Growing evidence indicates that ubiquitination of RTKs is critical for their lysosomal degradation, through their ubiquitin-dependent targeting to intralumenal vesicles of MVBs and lysosomal degradation (Urbe et al, 2000;Raiborg et al, 2002;Duan et al, 2003;Jiang et al, 2003;Yamasaki et al, 2003). RTKs, including Met, may undergo multimonoubiquitination and Lys63-linked polyubiquitination, both of which do not form a signal for proteasomal degradation (Haglund et al, 2003;Mosesson et al, 2003;Carter et al, 2004;Huang et al, 2006).…”

Section: Regulation Of Met Downregulation: Consequence For Oncogenicmentioning

confidence: 99%

From Tpr-Met to Met, tumorigenesis and tubes

2007

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The receptor for hepatocyte growth factor (HGF)/scatter factor (SF), Met, controls a program of invasive epithelial growth through the coordination of cell proliferation and survival, cell migration and epithelial morphogenesis. This process is important during embryogenesis and for organ regeneration in the adult. However, when deregulated the HGF/SF-Met signaling axis contributes to tumorigenesis and metastasis. Studies on the oncogenic activation of the Met receptor have shed light on the molecular mechanisms underlying the oncogenic activation of receptor tyrosine kinase (RTKs). More than a decade ago, work on the Met related oncogene, Tpr-Met, revealed the mechanism for activation of RTK-derived oncogenes generated following chromosomal translocation. More recently, studies on the mechanisms of downregulation of the Met RTK highlight a role for loss of downregulation in RTK oncogenic activation.

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Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes

Cited by 646 publications

References 30 publications

Ent5p Is Required with Ent3p and Vps27p for Ubiquitin-dependent Protein Sorting into the Multivesicular Body

Ent5p Is Required with Ent3p and Vps27p for Ubiquitin-dependent Protein Sorting into the Multivesicular Body

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

From Tpr-Met to Met, tumorigenesis and tubes

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