A Ubiquitin-interacting Motif (UIM) Is Essential for Eps15 and Eps15R Ubiquitination

Klapisz, Elsa; Sorokina, Irina; Lemeer, Simone; Pijnenburg, M. A. P.; Verkleij, Arie J.; Henegouwen, Paul M.P. van Bergen en

doi:10.1074/jbc.m203004200

Cited by 91 publications

(86 citation statements)

References 46 publications

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“…EpsinR shows preference for binding to PtdIns(4)P and PtdIns(5)P in vitro (144,235), which is consistent with the finding that PtdIns(4)P is abundant on Golgi membranes (372). Epsin and EpsinR contain a ubiquitin binding domain just COOH terminal to the ENTH domain and are themselves monoubiquitylated (146,182,259,276). Ubiquitylation of hormone receptors (202,210), as well as certain other membrane proteins (108), is necessary for sorting them in early endosomes from the recycling to the degradative pathway.…”

Section: Enth/anth Domainssupporting

confidence: 73%

Phosphoinositides in Constitutive Membrane Traffic

Roth

2004

Physiological Reviews

263

267

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Proteins that make, consume, and bind to phosphoinositides are important for constitutive membrane traffic. Different phosphoinositides are concentrated in different parts of the central vacuolar pathway, with phosphatidylinositol 4-phosphate predominate on Golgi, phosphatidylinositol 4,5-bisphosphate predominate at the plasma membrane, phosphatidylinositol 3-phosphate the major phosphoinositide on early endosomes, and phosphatidylinositol 3,5-bisphosphate found on late endocytic organelles. This spatial segregation may be the mechanism by which the direction of membrane traffic is controlled. Phosphoinositides increase the affinity of membranes for peripheral membrane proteins that function for sorting protein cargo or for the docking and fusion of transport vesicles. This implies that constitutive membrane traffic may be regulated by the mechanisms that control the activity of the enzymes that produce and consume phosphoinositides. Although the lipid kinases and phosphatases that function in constitutive membrane traffic are beginning to be identified, their regulation is poorly understood.

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Section: Enth/anth Domainssupporting

confidence: 73%

Phosphoinositides in Constitutive Membrane Traffic

Roth

2004

Physiological Reviews

263

267

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“…In mammalian cells, several proteins that are involved in clathrin-mediated endocytosis, such as epsin, Eps15, and Hrs, have been shown to be ubiquitinated (van Delft et al, 1997;Klapisz et al, 2002;Polo et al, 2002). These proteins carry ubiquitin-interacting motifs (Hofmann and Falquet, 2001) that also seem to be intimately linked with their ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

The Deubiquitinating Enzyme Ubp1 Affects Sorting of the ATP-binding Cassette-Transporter Ste6 in the Endocytic Pathway

Schmitz

Kinner

Kölling

2005

MBoC

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Deubiquitinating enzymes (Dubs) are potential regulators of ubiquitination-dependent processes. Here, we focus on a member of the yeast ubiquitin-specific processing protease (Ubp) family, the Ubp1 protein. We could show that Ubp1 exists in two forms: a longer membrane-anchored form (mUbp1) and a shorter soluble form (sUbp1) that seem to be independently expressed from the same gene. The membrane-associated mUbp1 variant could be localized to the endoplasmic reticulum (ER) membrane by sucrose density gradient centrifugation and by immunofluorescence microscopy. Overexpression of the soluble Ubp1 variant stabilizes the ATP-binding cassette-transporter Ste6, which is transported to the lysosome-like vacuole for degradation, and whose transport is regulated by ubiquitination. Ste6 stabilization was not the result of a general increase in deubiquitination activity, because overexpression of Ubp1 had no effect on the degradation of the ER-associated degradation substrate carboxypeptidase Y* and most importantly on Ste6 ubiquitination itself. Also, overexpression of another yeast Dub, Ubp3, had no effect on Ste6 turnover. This suggests that the Ubp1 target is a component of the protein transport machinery. On Ubp1 overexpression, Ste6 accumulates at the cell surface, which is consistent with a role of Ubp1 at the internalization step of endocytosis or with enhanced recycling to the cell surface from an internal compartment. INTRODUCTIONMany cellular proteins are modified by the attachment of the 76-amino acid polypeptide ubiquitin (Hochstrasser, 1996;Hershko and Ciechanover, 1998). The main role of ubiquitination is to target proteins for degradation either directly by acting as a degradation signal that is recognized by the 26S proteasome or indirectly by sorting membrane proteins into the lysosomal/vacuolar degradation pathway (Hicke, 1999). Ubiquitination of substrate proteins, which occurs by a cascade of enzymatic reactions, is reversible. Ubiquitin can again be removed from proteins by deubiquitinating enzymes (Dubs). A large number of Dubs have been identified in various organisms that are either cysteine proteases or metalloproteases (Verma et al., 2002; Yao and Cohen, 2002). The more classical cysteine proteases can again be divided into two groups: the ubiquitin C-terminal hydrolases (Uchs) that preferentially cleave ubiquitin from peptides and small adducts (e.g., Yuh1 in yeast) and the extremely divergent family of ubiquitin-specific processing proteases (Ubps) that cleave ubiquitin from protein substrates (Hochstrasser, 1996). Of the 17 cysteine-protease-type Dubs in yeast 16 belong to the Ubp class.The degree of ubiquitination seems to be mainly regulated at the level of ubiquitin attachment. However, evidence is accumulating that deubiquitination also can be important for the regulation of ubiquitination levels. Evidence has been presented that the deubiquitinating enzyme Fat facets (Faf), which is involved in eye development in Drosophila, acts as a substrate-specific regulator of ubiquitination of the...

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“…The UIM motif in these proteins not only binds ubiquitin but also directs self monoubiquitylation, as will be discussed below Klapisz et al, 2002;Oldham et al, 2002;Polo et al, 2002;Raiborg et al, 2002;Shih et al, 2002). UIM-mediated binding may enable these adaptor proteins to couple ubiquitylated cargo with the machinery directing various stages of endocytosis, perhaps with Epsins and Eps15 functioning at the plasma membrane, and Hgs, as well as STAM, functioning at early endosomes and MVB.…”

Section: The Endocytic Machinery: An Assembly Of Ubiquitinbinding Coamentioning

confidence: 99%

“…Many components of the endocytic machinery have been shown to be ubiquitylated. The UIM-containing proteins Epsins, Eps15, Hgs and STAM are ubiquitylated in a UIM-dependent manner, at a site distinct from the domain itself Klapisz et al, 2002;Oldham et al, 2002;Polo et al, 2002;Raiborg et al, 2002;Shih et al, 2002). These domains do not possess intrinsic E3 ligase activity, but they must recruit an E3.…”

Section: Ubiquitylation Of the Endocytic Machinery: Possible Roles Inmentioning

confidence: 99%

Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases

2004

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A Ubiquitin-interacting Motif (UIM) Is Essential for Eps15 and Eps15R Ubiquitination

Cited by 91 publications

References 46 publications

Phosphoinositides in Constitutive Membrane Traffic

Phosphoinositides in Constitutive Membrane Traffic

The Deubiquitinating Enzyme Ubp1 Affects Sorting of the ATP-binding Cassette-Transporter Ste6 in the Endocytic Pathway

Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases

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