Ubiquitination on Nonlysine Residues by a Viral E3 Ubiquitin Ligase

Cadwell, Ken; Coscoy, Laurent

doi:10.1126/science.1110340

Cited by 366 publications

(334 citation statements)

References 16 publications

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“…7A and B). In this regard, several reports have previously demonstrated that nonlysine residues, including cysteines, serines and threonines, can also serve as ubiquitin acceptor sites or that ubiquitination can occur on the N-terminal residue of the substrate (11,14,41,83,88). Hence, we conclude that while Dok-1 lysine residues are major Dok-1 ubiquitylation sites, other nonlysine Dok-1 residues could also contribute to Dok-1 ubiquitination.…”

Section: Resultsmentioning

confidence: 79%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

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Section: Resultsmentioning

confidence: 79%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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“…Abbreviations: ex, expression; GalT1, ␤1,4-galactosyltransferase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GTAP, galactosyltransferase-associating protein; ICM, inner cell mass; IP, immunoprecipitation; siRNA, small interference RNA; Ub, ubiquitinated. ported for other receptors, which also lack accessible lysines in their cytoplasmic domains [32]. This type of ubiquitination is much more labile than the commonly formed Ub-isopeptide bond and, hence, would have escaped detection in our system.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Novel Ubiquitin-Conjugating Enzyme That Regulates β1,4-Galactosyltransferase-1 in Embryonic Stem Cells

Wassler¹,

Shur

Zhou³

et al. 2008

Stem Cells

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In this study we identified a novel galactosyltransferase 1-associating protein (GTAP) by cDNA cloning from a murine embryonic cDNA library using the two-hybrid yeast system. GTAP is expressed in early embryonic tissues, as well as in adult tissues with active cell turnover, and belongs to the class III ubiquitin-conjugating (E2) enzyme family. Its COOH-terminal domain contains a consensus sequence for ubiquitin binding shared by all the ubiquitin-conjugating enzymes, whereas its NH 2 -terminal domain appears critical for the binding and internalization of cell surface galactosyltransferase 1 (GalT1) in embryonic stem cells through a monensin-and MG132-dependent pathway. We have found that GTAP regulates GalT1-associated, laminin-dependent embryonic cell adhesion and the formation of embryoid bodies. Thus, GTAP functions as an evolutionarily conserved E2 enzyme, which may participate in intercellular adhesion and embryonic development. STEM CELLS 2008;

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“…The same group recently reported that MIR1, but not MIR2, promoted downregulation of MHC I molecules lacking lysine residues in their intracytoplasmic domain. In the presence of MIR1, these MHC I molecules were ubiquitinated, and their association with ubiquitin was sensitive to β-mercaptoethanol, unlike lysine-ubiquitin bonds [109]. Similarly, the RING-finger proteins MBP-IAP2, IE2, and PE38 of Bombyx mori nucleopolyhedrovirus (BmNPV) are able to reconstitute ubiquitination activity in vitro and their activity is dependent on their RING-finger motif [110].…”

Section: Pathogen-derived Proteins Act As E3 Ligases In Host Cellsmentioning

confidence: 99%

Ubiquitination-mediated protein degradation and modification: an emerging theme in plant-microbe interactions

et al. 2006

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Post-translational modification is central to protein stability and to the modulation of protein activity. Various types of protein modification, such as phosphorylation, methylation, acetylation, myristoylation, glycosylation, and ubiquitination, have been reported. Among them, ubiquitination distinguishes itself from others in that most of the ubiquitinated proteins are targeted to the 26S proteasome for degradation. The ubiquitin/26S proteasome system constitutes the major protein degradation pathway in the cell. In recent years, the importance of the ubiquitination machinery in the control of numerous eukaryotic cellular functions has been increasingly appreciated. Increasing number of E3 ubiquitin ligases and their substrates, including a variety of essential cellular regulators have been identified. Studies in the past several years have revealed that the ubiquitination system is important for a broad range of plant developmental processes and responses to abiotic and biotic stresses. This review discusses recent advances in the functional analysis of ubiquitination-associated proteins from plants and pathogens that play important roles in plant-microbe interactions.

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Ubiquitination on Nonlysine Residues by a Viral E3 Ubiquitin Ligase

Cited by 366 publications

References 16 publications

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Characterization of a Novel Ubiquitin-Conjugating Enzyme That Regulates β1,4-Galactosyltransferase-1 in Embryonic Stem Cells

Ubiquitination-mediated protein degradation and modification: an emerging theme in plant-microbe interactions

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