The ESCRT (endosomal sorting complex required for transport) machinery plays a critical role in receptor down-regulation, retroviral budding, and other normal and pathological processes. The ESCRT components are conserved in all five major subgroups of eukaryotes. This review summarizes the growing number of links identified between ESCRT-mediated protein sorting in the MVB (multivesicular body) pathway and various human diseases.

The MVB (multivesicular body) sorting pathway

The endocytic down-regulation of numerous signalling receptors such as the EGFR (epidermal growth factor receptor) plays an important role in modulating the amplitude and kinetics of the signalling pathways they activate and thus the maintenance of normal cellular homoeostasis. Following internalization, the critical decisions regarding the fate of these receptors are made at the level of the endosome. At the early endosome, a signalling receptor is sorted into one of two trafficking pathways: it is either recycled back to the cell surface (receptor sequestration) or sorted into the MVB pathway for lysosomal degradation (receptor down-regulation).

In yeast and in humans, proteins that function in the MVB pathway (receptor down-regulation pathway) are referred to as class E Vps (vacuolar protein sorting) proteins. The majority of the class E Vps proteins are constituents of three separate protein complexes called ESCRT (endosomal sorting complex required for transport) -I, -II and -III that function sequentially in sorting proteins into the MVB pathway. A combination of genetic and biochemical analyses of the ESCRTs in yeast has resulted in a model for the function of the class E proteins in the MVB pathway (Figure 1) (summarized in reviews [13]). The ubiquitinated endosomal cargo is first recognized and bound by Vps27 at the membrane. In the next step, cargo is bound by ESCRT-I, and ESCRT-II is recruited to the membrane via a combination of protein–lipid and protein–protein (ESCRT-I–ESCRT-II and ESCRT-II–ubiquitin) interactions. ESCRT-II in turn initiates the oligomerization of at least four soluble small coiled-coil proteins (Vps20, Snf7, Vps24 and Vps2), resulting in the assembly of a large endosome-associated structure: ESCRT-III. The oligomeric nature of ESCRT-III has been proposed to facilitate cargo concentration before membrane deformation and vesicle formation. ESCRT-III is also responsible for recruiting the deubiquitinating enzyme Doa4, which catalyses the removal of the ubiquitin tag before cargo sorting into MVB vesicles. Following protein sorting into MVB vesicles, ESCRT-III is bound by a multimeric AAA (ATPase associated with various cellular activities), Vps4, that disassembles ESCRT-III in an ATP-dependent manner and recycles its four constituent proteins into the cytosol for further rounds of cargo sorting. The dynamics and regulation of the ESCRT machinery have been the focus of several excellent reviews [13], but here we focus on the endocytic and non-endocytic functions of the ESCRTs in cellular pathogenesis.

The MVB sorting pathway

Figure 1
The MVB sorting pathway

Sorting of ubiquitinated proteins in the MVB pathway involves sequential interactions of the cargo protein with the Vps27–Hse1 (has symptoms of class E mutants 1), ESCRT-I, ESCRT-II and ESCRT-III complexes. ESCRT-III forms a membrane-bound protein lattice responsible for membrane deformation and the generation of intraluminal MVB vesicles. Fusion of the MVB with the lysosome delivers the intraluminal vesicles and their contents for lysosomal degradation.

Figure 1
The MVB sorting pathway

Sorting of ubiquitinated proteins in the MVB pathway involves sequential interactions of the cargo protein with the Vps27–Hse1 (has symptoms of class E mutants 1), ESCRT-I, ESCRT-II and ESCRT-III complexes. ESCRT-III forms a membrane-bound protein lattice responsible for membrane deformation and the generation of intraluminal MVB vesicles. Fusion of the MVB with the lysosome delivers the intraluminal vesicles and their contents for lysosomal degradation.

ESCRT-mediated receptor down-regulation in cancer

RTKs (receptor tyrosine kinases) are important regulators of intercellular communication controlling cell growth, proliferation, differentiation, survival and metabolism in a variety of tissues and organs [4,5]. Consequently, dysfunctions in the action of RTKs or aberrations in the activities and cellular localization of key components of the downstream signalling pathways that they activate result in severe pathological conditions, such as cancer, diabetes, immune deficiencies and cardiovascular diseases, among many others [6] (Table 1). EGFR is one of the best-studied RTKs, and its excessive signalling is associated with the development of a variety of human cancers, including mammary carcinomas, squamous carcinomas and glioblastomas, as well as other malignant diseases [6]. The MVB pathway terminates receptor signalling via lysosomal degradation of the receptor, and thus plays an important role in modulating the amplitude and kinetics of various signalling pathways from activated receptors [13]. Consequently, studies in Drosophila have shown that EGFR degradation is impaired by the inactivation of Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), Tsg101 (tumour susceptibility gene 101) or Vps25 [710]. In mammals, the effect of depleting Hrs or STAM (signal-transducing adaptor molecule) 1 and STAM2 is much milder than that of depleting Tsg101, which causes a severe defect in EGFR degradation. Interestingly, Tsg101 and another mammalian ESCRT-I component, Vps37A, were originally identified as tumour-suppressor genes that map to chromosomal regions that are often deleted or mutated in cancers [11,12]. There is growing evidence that Vps37A and Tsg101 function as putative tumour suppressors. Cells with reduced expression of Tsg101 form metastatic tumours in nude mice [11], and aberrant Tsg101 transcripts have been observed in many cases of acute myeloid leukaemia and human prostate cancer, although their correlation with carcinogenesis has remained controversial [13]. Vps37A expression is reduced or absent in hepatocellular carcinomas, and Vps37A is involved directly in suppressing uncontrolled proliferation and invasion of hepatocellular carcinoma cell lines [12]. This growth inhibitory role of Vps37A in the case of hepatocellular carcinomas has earned it the name of HCRP1 (hepatocellular carcinoma-related protein 1).

Table 1
Summary of the diseases in humans associated with the MVB pathway

FTLD-U, frontotemporal lobar dementia with ubiquitin-immunoreactive inclusions; HRCP1, hepatocellular carcinoma-related protein 1; Hse1, has symptoms of class E mutants 1.

Complex Component Disease Defect 
Vps27–Hse1 (Hrs–STAM) Vps27 (Hrs) Cancer (mammary carcinomas, squamous carcinomas, glioblastomas) EGFR degradation 
ESCRT-I Vps23 (Tsg101) Cancer (acute myeloid leukaemia, human prostate cancer) EGFR degradation 
ESCRT-I Vps23 (Tsg101) Cancer (breast, cervical cancer, gastrointestinal cancer) Alteration in levels of cell-cycle-control proteins 
ESCRT-I Vps37/HCRP1 (Vps37A) Hepatocellular carcinoma EGFR degradation 
ESCRT-I (Tsg101)-interacting Mahogunin Spongiform neurodegeneration Defective ubiquitination 
ESCRT-III Vps2 (CHMP2B) FTD3/FTLD-U, ALS (neurodegeneration) Disruption of endosomal trafficking 
ESCRT-III Vps24 (CHMP3) HD, Parkinson's disease Defects in autophagic clearance 
ESCRT-III mSnf7-1 Neurodegeneration ESCRT-III dysfunction and autophagosome accumulation 
ESCRT-III (CHMP1B)-interacting Spastin HSP Unknown 
ESCRT-I, ESCRT-III-associated Tsg101 (Vps23) and Alix (Bro1) AIDS and retroviral infections Viral budding via the MVB pathway 
ESCRT-III Snf7 (CHMP4B) Cataract Defects in endosomal trafficking and maintenance of lens transparency 
ESCRT-I (Tsg101)-interacting CD2AP Focal segmental glomerulosclerosis Defects in MVB formation in podocytes 
Complex Component Disease Defect 
Vps27–Hse1 (Hrs–STAM) Vps27 (Hrs) Cancer (mammary carcinomas, squamous carcinomas, glioblastomas) EGFR degradation 
ESCRT-I Vps23 (Tsg101) Cancer (acute myeloid leukaemia, human prostate cancer) EGFR degradation 
ESCRT-I Vps23 (Tsg101) Cancer (breast, cervical cancer, gastrointestinal cancer) Alteration in levels of cell-cycle-control proteins 
ESCRT-I Vps37/HCRP1 (Vps37A) Hepatocellular carcinoma EGFR degradation 
ESCRT-I (Tsg101)-interacting Mahogunin Spongiform neurodegeneration Defective ubiquitination 
ESCRT-III Vps2 (CHMP2B) FTD3/FTLD-U, ALS (neurodegeneration) Disruption of endosomal trafficking 
ESCRT-III Vps24 (CHMP3) HD, Parkinson's disease Defects in autophagic clearance 
ESCRT-III mSnf7-1 Neurodegeneration ESCRT-III dysfunction and autophagosome accumulation 
ESCRT-III (CHMP1B)-interacting Spastin HSP Unknown 
ESCRT-I, ESCRT-III-associated Tsg101 (Vps23) and Alix (Bro1) AIDS and retroviral infections Viral budding via the MVB pathway 
ESCRT-III Snf7 (CHMP4B) Cataract Defects in endosomal trafficking and maintenance of lens transparency 
ESCRT-I (Tsg101)-interacting CD2AP Focal segmental glomerulosclerosis Defects in MVB formation in podocytes 

Recent studies examining the role of ESCRT-II and ESCRT-III components in EGFR degradation have yielded interesting results. Although CHMP (charged multivesicular body protein) 3/hVps (human Vps) 24 (ESCRT-III) deletion induces a delay in EGFR degradation, it does not cause sustained signalling, possibly because such signalling is already terminated before ESCRT-III is engaged [14]. A similar degradation delay with proper signal silencing has been reported for the ESCRT-II component EAP30 [15]. In contrast, depletion of Hrs, Tsg101 or Vps25 led to sustained EGFR signalling, presumably because signalling-competent receptors have increased residence time in the limiting membrane of the endosomes that allows recycling of the receptors to the plasma membrane [710]. Furthermore, these studies suggest that ESCRT-I plays a particularly important role in signal termination on endosomes, and also help explain the fact that none of the ESCRT-III subunits has so far been implicated in cancer.

Mutations that uncouple EGFR from c-Cbl-mediated ubiquitination and thereby from ESCRT-mediated down-regulation are tightly associated with the pathogenesis of cancer. For instance, a mutant EGFR lacking only the direct c-Cbl-binding site transduces stronger mitogenic signals than the wild-type receptor [16]. Interestingly, the most oncogenic member of the ErbB family, HER2, lacks a c-Cbl-binding site and thus seems unlikely to be regulated by the ESCRT machinery.

The c-Met RTK regulates invasive growth, a complex cellular programme that is critical for normal development and wound repair. Invasive growth is frequently co-opted by tumours to promote their own growth, motility and invasion, and, consequently, c-Met is overexpressed in a variety of human cancers [17]. Cellular c-Met levels are governed in part by c-Cbl-mediated ubiquitination and degradation, and a mutant of c-Met defective in ubiquitination has transforming activity in fibroblast and epithelial cells [18]. Clearly, ubiquitination and the ESCRT pathway are critical to avoid c-Met-related malignant transformation.

The Notch signalling pathway plays a central role in animal growth and patterning, and its deregulation leads to many human diseases, including cancers [19]. Studies in Drosophila have shown that Notch co-localizes with Rab5 and Rab7 and is degraded by the lysosomes, suggesting a possible involvement of the ESCRT machinery in the regulation of Notch signalling. Depletion of hrs, erupted (TSG101) and vps25 leads to accumulation of the cell-surface receptors Notch, Delta, Thickveins and EGFR [710]. Notch accumulation induces cell proliferation in the eye disc [2022] and gives rise to overgrowth phenotypes in surrounding wild-type cells via the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway [79]. Furthermore, clonal inactivation of ESCRTs in Drosophila results in loss of epithelial cell polarity, another phenotype associated with malignant transformation [79], suggesting that ESCRT components are involved in organizing the actin and/or microtubule cytoskeleton. In summary, there is a growing body of evidence that indicates an important role for functional ESCRTs in suppressing malignant transformation.

Non-endosomal functions of ESCRTs in cancer

ESCRTing abscission at the midbody

Cytokinesis in mammalian cells consists of at least three distinct steps: assembly of the central spindle, formation of the cleavage furrow and the final abscission at the midbody. Topologically, the final abscission step of cell division resembles the pinching-off step of MVB formation. Interestingly, a recent study in human cells found that the ESCRT-I subunit Tsg101 and the ESCRT-associated protein Alix [ALG-2 (apoptosis-linked gene 2)-interacting protein X] are recruited to the midbody during cytokinesis via an interaction with Cep55 (centrosome protein 55) [23]. Furthermore, Alix and Tsg101 bind a series of proteins involved in cytokinesis, including Cep55, CD2AP (CD2-associated protein), ROCK1 (Rho-associated kinase 1) and IQGAP1 (IQ motif-containing GTPase-activating protein 1) [24]. Vps4 and ESCRT-III proteins are also recruited to the midbody, indicating that much of the ESCRT machinery localizes to the midbody of dividing cells [24]. In addition, depletion of Alix and ESCRT-I inhibits cytokinesis resulting in the formation of multinuclear cells that are predisposed to developing aneuploidy and malignancies. A similar requirement of ESCRT-I (elc/tsg101) for efficient midbody abscission during cytokinesis has also been reported in Arabidopsis [25]. These data strongly suggest that the ESCRT machinery may be involved in tumour pathogenesis arising from defects in cytokinesis. However, the precise function and generality of the ESCRT machinery in eukaryotic cell cytokinesis remains an open question. The ESCRT proteins are not essential for division in Saccharomyces cerevisiae [2], thereby questioning a more universal role for the ESCRTs in cytokinesis. Furthermore, Morita et al. [24] have reported that even mammalian cells may differ in their requirements for cytokinesis, since HEK-293T (human embryonic kidney) cells continue to divide following CEP55 deletion. Additional work is required to discern whether the ESCRT pathway plays a fundamental role in the division of all mammalian cells and whether this role is direct (by facilitating the actual abscission process) or indirect (by functioning in vesicular trafficking and/or membrane protein degradation).

Cell-cycle control and tumour maintenance

The ESCRT-I components Tsg101 and Vps37A have been considered to function as tumour-suppressor genes because their genetic loci map to chromosomal regions that are often deleted or mutated in malignancies (described above). However, several studies indicate that Tsg101 plays a role in cell-cycle control and performs a tumour-maintenance function [26]. Tsg101 depletion results in cellular accumulation of p53 and p21, two negative regulators of the cell cycle. Furthermore, Tsg101 reduces cellular levels of p53 via lysosomal degradation by stimulating its ubiquitination by an E3 ligase, MDM2 (murine double minute 2) [27]. These data indicate that Tsg101 is essential for cell proliferation, a conclusion that is in contradiction to the tumour-suppressor properties of Tsg101 (discussed above). Additional experimentation will be required to more precisely determine the role of Tsg101 in cancer pathogenesis.

ESCRTs and neurodegeneration

Neurons take up macromolecules from the extracellular environment via endocytosis, with early endosomes receiving endocytosed materials from the cell surface via fusion with clathrin-coated vesicles. Endocytosis is required for the re-uptake of synaptic vesicles during synaptic transmission and after neuronal damage, the efficient supply and uptake of lipid molecules is critical for neuronal repair and survival [28]. Furthermore, homoeostasis of plasma membrane protein composition and organization (channels and pumps) in neurons relies on endocytic down-regulation via the MVB pathway. Consequently, compared with other cell types, neurons are particularly vulnerable to defects in the endosomal–lysosomal system, and aberrant endosomal trafficking has been linked to a number of neurodegenerative diseases. For instance, endosomal abnormalities are among the earliest pathological features of AD (Alzheimer's disease), preceding the classical pathological markers of β-amyloid plaque deposition and neurofibrillary tangles [29]. Also, mutations in alsin (encoded by ALS2), the GEF (guanine-nucleotide-exchange factor) for the endosomal fusion regulator Rab5 have been shown to cause ALS (amyotrophic lateral sclerosis) [30].

A single splice site mutation in CHMP2B (hVps2) causes a rare form of autosomal dominant FTD (frontotemporal dementia), FTD3 (FTD linked to chromosome 3), in a large Danish pedigree [31]. Interestingly, mutations in CHMP2B have also been observed in some patients with ALS. FTD is the second most common form of presenile dementia after AD [32] and is characterized neuropathologically by the presence of tau or ubiquitin pathology, the latter referred to as FTLD-U (frontotemporal lobar dementia with ubiquitin-immunoreactive inclusions) [33]. The cytosolic ubiquitin-positive deposits found in the brains of FTD3 patients are also positive for p62/sequestosome-1, a common component of protein inclusions associated with neurodegenerative diseases [34]. p62 binds polyubiquitin through its UBA (ubiquitin-pathway-associated) domain and interacts with the autophagic protein LC3 (light chain 3)/Atg8, thereby providing a possible link between protein aggregation and autophagic clearance. This raises an important question: how are defects in the ESCRT machinery linked to the formation of ubiquitin-positive inclusions and development of neurodegenerative disease? One possibility is that the endosomes might provide membranes and/or important proteins for autophagic sequestration. ESCRT dysfunction results in accumulation of membranes in the class E compartment, and in so doing prevents the formation of the autophagic phagophore. Another possibility is that autophagic sequestration is blocked when the downstream degradative MVB pathway is dysfunctional (negative feedback), leading to the accumulation of misfolded protein aggregates in the cytosol.

A number of neurodegenerative diseases, such as HD (Huntington's disease) and Parkinson's disease, are characterized by the accumulation of intracellular ubiquitinated protein aggregates. In some cases of HD and spinocerebellar ataxia, the intracellular protein aggregates are characterized by the presence of polyglutamine expansion tracts [35]. A recent study has shown that functional MVBs and Vps24 are required for efficient autophagic clearance of Htt (huntingtin) polyglutamine aggregates, in both human HeLa and mouse neuronal cells [36]. These observations indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.

Compromised ESCRT function may also be involved in other neurodegenerative processes. For instance, the ESCRT-I subunit Tsg101 was shown recently to be a substrate of the E3 ubiquitin ligase mahogunin [37]. Interestingly, null mutation of mahogunin has been shown to cause spongiform neurodegeneration, a recessively transmitted prion-like disease in mice [37]. Another recent study has shown that the ESCRT-III protein mSnf7-2 is highly expressed in most, but not all, neurons and is essential for neuronal structural integrity and viability [38]. The authors report that CHMP2B (hVps2) itself is not required for neuronal viability, probably compensated for by its paralogue CHMP2A. However, the splice site mutant of CHMP2B that causes FTD forms abnormal complexes with mSnf7-2, resulting in the failure of ESCRT-III to dissociate from endosomes and rapid neuronal cell loss, suggesting a novel mechanism of neurodegeneration. Also, the microtubule-severing protein spastin has been shown to bind the ESCRT-III protein CHMP1B [39]. Spastin is encoded by SPG4, which is mutated in the most common form of HSP (hereditary spastic paraplegia). The importance of spastin's association with an ESCRT-III protein in the context of HSP remains to be resolved. Furthermore, overexpression of Alix [40], or targeted disruption of the gene encoding STAM1 or AMSH [associated molecule with the SH3 (Src homology 3) domain of STAM] [41,42] has been shown to affect neuronal cell viability especially in the hippocampus and cerebral cortex.

ESCRTs and other cellular pathologies

Bacterial infections

A recent report has shown that components of the ESCRT machinery restrict mycobacterial growth, although the growth inhibition mechanism remains to be defined [43]. It is possible that the ESCRT machinery might be required for delivery of the bacteria to the lysosome, and, in its absence, the bacteria reside in an earlier more permissive compartment. Alternatively, in cells that lack ESCRT components, bacteria may traffic to the lysosome, but lysosomal constituents may not be properly localized, thereby providing a more permissive environment for bacterial growth. Although the study by Philips et al. [43] was performed using the model mycobacterial pathogen Mycobacterium fortuitum, ESCRT components can now be considered as therapeutic targets for the treatment of Mycobacterium tuberculosis which causes 2–3 million deaths every year.

Cardiac and renal defects

Other than signalling receptors, the MVB pathway also mediates the lysosomal degradation of ion channels, and thus plays a critical role in the maintenance of ion homoeostasis in different tissues. This is clearly demonstrated in the case of the renal ENaC (epithelial sodium channel), where abnormalities in channel opening and number (defect in endocytic down-regulation) have been linked to several genetic disorders, including cystic fibrosis, pseudohypoaldosteronism type I and Liddle's syndrome [4446]. Subtle dysregulation of ENaC may also be important in essential hypertension, a common condition and a major cause of cardiovascular morbidity and mortality.

Mutations that ablate expression of one CD2AP (Tsg101-interacting protein) allele cause death in mice at 6 weeks of age and FSGS (focal segmental glomerulosclerosis) in humans [47]. Electron microscopic analysis of podocytes from CD2AP+/− mice revealed defects in the formation of MVBs, suggesting an impairment of the intracellular degradation pathway. There is growing evidence that not only may glomerular disease involve autoimmune antibodies or immune complexes, but also protein clearance by podocytes may be an important modulator and perhaps instigator of disease. Hence, many renal diseases may be caused by defects in intracellular trafficking.

HIV and retroviral infection

Outside of pathophysiological diseases, multiple classes of enveloped viruses utilize the ESCRT machinery for budding out of host cells. Efficient release of HIV requires an interaction between Tsg101 and the ‘late domain’ found in the p6 domain of all HIV Gag proteins, and also in structural proteins of other pathogenic human viruses, including Ebola and HTLV (human T-lymphotropic virus) ([48,49] and reviewed in [50]). Clearly, a mechanistic understanding of the ESCRT machinery can be useful in the design of antiviral therapeutics.

Conclusions and future perspectives

As outlined in the present paper, the number of links between ESCRT-mediated protein degradation in the lysosome and human disease is steadily and rapidly growing. With these links being established, the stage is set for the design of preventive and therapeutic strategies. It is truly amazing to see that the ESCRTs identified using yeast genetics continue to have such a profound impact on our thinking about the molecular basis of human diseases and our tireless quest to fight them.

ESCRTs: from Cell Biology to Pathogenesis: Biochemical Society Focused Meeting held at Robinson College, Cambridge, U.K., 26–28 August 2008. Organized and Edited by Katherine Bowers (University College London, U.K.), Juan Martin-Serrano (King's College London, U.K.) and Paul Whitley (Bath, U.K.).

Abbreviations

     
  • AD

    Alzhheimer's disease

  •  
  • Alix

    ALG-2 (apoptosis-linked gene 2)-interacting protein X

  •  
  • ALS

    amyotrophic lateral sclerosis

  •  
  • CD2AP

    CD2-associated protein

  •  
  • Cep55

    centrosome protein 55

  •  
  • CHMP

    charged multivesicular body protein

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • ENaC

    epithelial sodium channel

  •  
  • ESCRT

    endosomal sorting complex required for transport

  •  
  • FTD

    frontotemporal dementia

  •  
  • FTD3

    FTD linked to chromosome 3

  •  
  • HD

    Huntington's disease

  •  
  • Hrs

    hepatocyte growth factor-regulated tyrosine kinase substrate

  •  
  • HSP

    hereditary spastic paraplegia

  •  
  • MVB

    multivesicular body

  •  
  • RTK

    receptor tyrosine kinase

  •  
  • STAM

    signal-transducing adaptor molecule

  •  
  • Tsg101

    tumour susceptibility gene 101

  •  
  • Vps

    vacuolar protein sorting

  •  
  • hVps

    human Vps

We thank members of the Emr laboratory for helpful discussions.

Funding

S.S. is supported by a fellowship from the American Heart Association [grant number AHA 0826060D].

References

References
1
Saksena
S.
Sun
J.
Chu
T.
Emr
S.D.
ESCRTing proteins in the endocytic pathway
Trends Biochem. Sci.
2007
, vol. 
32
 (pg. 
561
-
573
)
2
Hurley
J.H.
Emr
S.D.
The ESCRT complexes: structure and mechanism of a membrane-trafficking network
Annu. Rev. Biophys. Biomol. Struct.
2006
, vol. 
35
 (pg. 
277
-
298
)
3
Williams
R.L.
Urbé
S.
The emerging shape of the ESCRT machinery
Nat. Rev. Mol. Cell Biol.
2007
, vol. 
8
 (pg. 
355
-
368
)
4
Hunter
T.
Signaling: 2000 and beyond
Cell
2000
, vol. 
100
 (pg. 
113
-
127
)
5
Pawson
T.
Gish
G.D.
Nash
P.
SH2 domains, interaction modules and cellular wiring
Trends Cell Biol.
2001
, vol. 
11
 (pg. 
504
-
511
)
6
Blume-Jensen
P.
Hunter
T.
Oncogenic kinase signaling
Nature
2001
, vol. 
411
 (pg. 
355
-
365
)
7
Thompson
B.J.
Mathieu
J.
Sung
H.H.
Loeser
E.
Rorth
P.
Cohen
S.M.
Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila
Dev. Cell
2005
, vol. 
9
 (pg. 
711
-
720
)
8
Vaccari
T.
Bilder
D.
The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking
Dev. Cell
2005
, vol. 
9
 (pg. 
687
-
698
)
9
Moberg
K.H.
Schelble
S.
Burdick
S.K.
Hariharan
I.K.
Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth
Dev. Cell
2005
, vol. 
9
 (pg. 
699
-
710
)
10
Lloyd
T.E.
Atkinson
R.
Wu
M.N.
Zhou
Y.
Pennetta
G.
Bellen
H.J.
Hrs regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila
Cell
2002
, vol. 
108
 (pg. 
261
-
269
)
11
Li
L.
Cohen
S.N.
Tsg101: a novel tumor susceptibility gene isolated by controlled homozygous functional knockout of allelic loci in mammalian cells
Cell
1996
, vol. 
85
 (pg. 
319
-
329
)
12
Xu
Z.
Liang
L.
Wang
H.
Li
T.
Zhao
M.
HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein
Biochem. Biophys. Res. Commun.
2003
, vol. 
311
 (pg. 
1057
-
1066
)
13
Bache
K.G.
Slagsvold
T.
Stenmark
H.
Defective downregulation of receptor tyrosine kinases in cancer
EMBO J.
2004
, vol. 
23
 (pg. 
2707
-
2712
)
14
Bache
K.G.
Stuffers
S.
Malerod
L.
Slagsvold
T.
Raiborg
C.
Lechardeur
D.
Walchli
S.
Lukacs
G.L.
Brech
A.
Stenmark
H.
The ESCRT-III subunit hVps24 is required for degradation but not silencing of the epidermal growth factor receptor
Mol. Biol. Cell
2006
, vol. 
17
 (pg. 
2513
-
2523
)
15
Malerod
L.
Stuffers
S.
Brech
A.
Stenmark
H.
Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation
Traffic
2007
, vol. 
8
 (pg. 
1617
-
1629
)
16
Waterman
H.
Katz
M.
Rubin
C.
Shtiegman
K.
Lavi
S.
Elson
A.
Jovin
T.
Yarden
Y.
A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling
EMBO J.
2002
, vol. 
21
 (pg. 
303
-
313
)
17
Haddad
R.
Lipson
K.E.
Webb
C.P.
Hepatocyte growth factor expression in human cancer and therapy with specific inhibitors
Anticancer Res.
2001
, vol. 
21
 (pg. 
4243
-
4252
)
18
Peschard
P.
Fournier
T.M.
Lamorte
L.
Naujokas
M.A.
Band
H.
Langdon
W.Y.
Park
M.
Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein
Mol. Cell
2001
, vol. 
8
 (pg. 
995
-
1004
)
19
Radtke
F.
Raj
K.
The role of Notch in tumorigenesis: oncogene or tumor suppressor?
Nat. Rev. Cancer
2003
, vol. 
3
 (pg. 
756
-
767
)
20
Chao
J.L.
Tsai
Y.C.
Chiu
S.J.
Sun
Y.H.
Localized Notch signal acts through eyg and upd to promote global growth in Drosophila eye
Development
2004
, vol. 
131
 (pg. 
3839
-
3847
)
21
Reynolds-Kenneally
J.
Mlodzik
M.
Notch signaling controls proliferation through cell-autonomous and non-autonomous mechanisms in the Drosophila eye
Dev. Biol
2005
, vol. 
285
 (pg. 
38
-
48
)
22
Tsai
Y.C.
Sun
Y.H.
Long-range effect of upd, a ligand for Jak/STAT pathway, on cell cycle in Drosophila eye development
Genesis
2004
, vol. 
39
 (pg. 
141
-
153
)
23
Carlton
J.G.
Martin-Serrano
J.
Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery
Science
2007
, vol. 
316
 (pg. 
1908
-
1912
)
24
Morita
E.
Sandrin
V.
Chung
H.Y.
Morham
S.G.
Gygi
S.P.
Rodesch
C.K.
Sundquist
W.I.
Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis
EMBO J.
2007
, vol. 
26
 (pg. 
4215
-
4227
)
25
Spitzer
C.
Schellmann
S.
Sabovljevic
A.
Shahriari
M.
Keshavaiah
C.
Bechtold
N.
Herzog
M.
Muller
S.
Hanisch
F.G.
Hulskamp
M.
The Arabidopsis elch mutant reveals functions of an ESCRT component in cytokinesis
Development
2006
, vol. 
133
 (pg. 
4679
-
4689
)
26
Carstens
M.J.
Krempler
A.
Triplett
A.A.
Van Lohuizen
M.
Wagner
K.U.
Cell cycle arrest and cell death are controlled by p53-dependent and p53-independent mechanisms in Tsg101-deficient cells
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
35984
-
35994
)
27
Li
L.
Liao
J.
Ruland
J.
Mak
T.W.
Cohen
S.N.
A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control
Proc. Natl. Acad. Sci. U.S.A.
2001
, vol. 
98
 (pg. 
1619
-
1624
)
28
Vance
J.E.
Campenot
R.B.
Vance
D.E.
The synthesis and transport of lipids for axonal growth and nerve regeneration
Biochim. Biophys. Acta
2000
, vol. 
1486
 (pg. 
84
-
96
)
29
Keating
D.J.
Chen
C.
Pritchard
M.A.
Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN1
Ageing Res. Rev.
2006
, vol. 
5
 (pg. 
388
-
401
)
30
Yang
Y.
Hentati
A.
Deng
H.X.
Dabbagh
O.
Sasaki
T.
Hirano
M.
Hung
W.Y.
Ouahchi
K.
Yan
J.
Azim
A.C.
, et al. 
The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis
Nat. Genet.
2001
, vol. 
29
 (pg. 
160
-
165
)
31
Skibinski
G.
Parkinson
N.J.
Brown
J.M.
Chakrabarti
L.
Lloyd
S.L.
Hummerich
H.
Nielsen
J.E.
Hodges
J.R.
Spillantini
M.G.
Thusgaard
T.
, et al. 
Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia
Nat. Genet.
2005
, vol. 
37
 (pg. 
806
-
808
)
32
Ratnavalli
E.
Brayne
C.
Dawson
K.
Hodges
J.R.
The prevalence and causes of dementia in people under the age of 65 years
Neurology
2002
, vol. 
58
 (pg. 
1615
-
1621
)
33
Neary
D.
Snowden
J.
Mann
D.
Frontotemporal dementia
Lancet Neurol.
2005
, vol. 
4
 (pg. 
771
-
780
)
34
Talbot
K.
Ansorge
O.
Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia linked to chromosome 3
Hum. Mol. Genet.
2006
, vol. 
15
 (pg. 
182
-
187
)
35
Iwata
A.
Christianson
J.C.
Bucci
M.
Ellerby
L.M.
Nukina
N.
Forno
L.S.
Kopito
R.R.
Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation
Proc. Natl. Acad. Sci. U.S.A.
2005
, vol. 
102
 (pg. 
13135
-
13140
)
36
Filimonenko
M.
Stuffers
S.
Raiborg
C.
Yamamoto
A.
Malerod
L.
Fisher
E.M.
Isaacs
A.
Brech
A.
Stenmark
H.
Simonsen
A.
Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease
J. Cell Biol.
2007
, vol. 
179
 (pg. 
485
-
500
)
37
Kim
B.Y.
Olzmann
J.A.
Barsh
G.S.
Chin
L.S.
Li
L.
Spongiform neurodegeneration-associated E3 ligase Mahogunin ubiquitylates TSG101 and regulates endosomal trafficking
Mol. Biol. Cell
2007
, vol. 
18
 (pg. 
1129
-
1142
)
38
Lee
J.A.
Beigneux
A.
Ahmad
S.T.
Young
S.G.
Gao
F.B.
ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration
Curr. Biol.
2007
, vol. 
17
 (pg. 
1561
-
1567
)
39
Reid
E.
Connell
J.
Edwards
T.L.
Duley
S.
Brown
S.E.
Sanderson
C.M.
The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B
Hum. Mol. Genet.
2005
, vol. 
14
 (pg. 
19
-
38
)
40
Trioulier
Y.
Torch
S.
Blot
B.
Cristina
N.
Chatellard-Causse
C.
Verna
J.M.
Sadoul
R.
Alix, a protein regulating endosomal trafficking, is involved in neuronal death
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
2046
-
2052
)
41
Ishii
N.
Owada
Y.
Yamada
M.
Miura
S.
Murata
K.
Asao
H.
Kondo
H.
Sugamura
K.
Loss of neurons in the hippocampus and cerebral cortex of AMSH-deficient mice
Mol. Cell. Biol.
2001
, vol. 
21
 (pg. 
8626
-
8637
)
42
Yamada
M.
Takeshita
T.
Miura
S.
Murata
K.
Kimura
Y.
Ishii
N.
Nose
M.
Sakagami
H.
Kondo
H.
Tashiro
F.
, et al. 
Loss of hippocampal CA3 pyramidal neurons in mice lacking STAM1
Mol. Cell. Biol.
2001
, vol. 
21
 (pg. 
3807
-
3819
)
43
Philips
J.A.
Porto
M.C.
Wang
H.
Rubin
E.J.
Perrimon
N.
ESCRT factors restrict mycobacterial growth
Proc. Natl. Acad. Sci. U.S.A.
2008
, vol. 
105
 (pg. 
3070
-
3075
)
44
Stutts
M.J.
Canessa
C.M.
Olsen
J.C.
Hamrick
M.
Cohn
J.A.
Rossier
B.C.
Boucher
R.C.
CFTR as a cAMP-dependent regulator of sodium channels
Science
1995
, vol. 
269
 (pg. 
847
-
850
)
45
Chang
S.S.
Grunder
S.
Hanukoglu
A.
Rösler
A.
Mathew
P.M.
Hanukoglu
I.
Schild
L.
Lu
Y.
Shimkets
R.A.
Nelson-Williams
C.
, et al. 
Mutations in the subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1
Nat. Genet.
1996
, vol. 
12
 (pg. 
248
-
253
)
46
Botero-Velez
M.
Curtis
J.J.
Warnock
D.G.
Brief report: Liddle's syndrome revisited
N. Engl. J. Med.
1994
, vol. 
330
 (pg. 
178
-
181
)
47
Kim
J.M.
Wu
H.
Green
G.
Winkler
C.A.
Kopp
J.B.
Miner
J.H.
Unanue
E.R.
Shaw
A.S.
CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility
Science
2003
, vol. 
300
 (pg. 
1298
-
1300
)
48
Freed
E.O.
Viral late domains
J. Virol.
2002
, vol. 
76
 (pg. 
4679
-
4687
)
49
Pornillos
O.
Alam
S.L.
Davis
D.R.
Sundquist
W.I.
Structure of Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein
Nat. Struct. Biol.
2002
, vol. 
9
 (pg. 
812
-
817
)
50
Demirov
D.G.
Freed
E.O.
Retrovirus budding
Virus Res.
2004
, vol. 
106
 (pg. 
87
-
102
)