Ubiquitination of serine, threonine, or lysine residues on the cytoplasmic tail can induce ERAD of MHC-I by viral E3 ligase mK3

Wang, Xiaoli; Herr, Roger A.; Chua, Wei Jen; Lybarger, Lonnie; Wiertz, Emmanuel J. H. J.; Hansen, Ted H.

doi:10.1083/jcb.200611063

Cited by 264 publications

(269 citation statements)

References 58 publications

(108 reference statements)

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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: 78%

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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: 78%

“…In general, proteins are targeted for proteasomal degradation by covalent attachment of polyubiquitin chains to their lysine residues, albeit other residues could also be involved (11,14,41,83,88). We found that proteasomal degradation of Dok-1 is largely mediated through ubiquitination of its lysine residues.…”

Section: Discussionmentioning

confidence: 82%

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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“…In a typical reaction, one of the at least 38 E2 enzymes interacts with activated ubiquitin and one of a near thousand E3 enzymes. The E3 then recognizes the target molecule and catalyzes the transfer of ubiquitin on a lysine or, less frequently, serine, cysteine, or threonine residues (1,(3)(4)(5). The E2/E3 combination and the localization of the complex confer the specificity to the reaction toward a given substrate (1,6).…”

mentioning

confidence: 99%

Autoregulation of MARCH1 Expression by Dimerization and Autoubiquitination

Bourgeois-Daigneault

Thibodeau

2012

The Journal of Immunology

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Some members of the membrane-associated RING-CH family of E3 ubiquitin ligases (MARCHs) are membrane-bound and target major players of the immune response. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs. It is induced by IL-10 and despite a strong increase in mRNA expression in human primary monocytes, the protein remains hardly detectable. To gain insights into the posttranslational regulation of MARCH1, we investigated whether its expression is itself regulated by ubiquitination. Our results demonstrate that MARCH1 is ubiquitinated in transfected human cell lines. Polyubiquitin chain-specific Abs revealed the presence of K48-linked polyubiquitin chains. A mutant devoid of lysine residues in the N- and C-terminal regions was less ubiquitinated and had a prolonged half-life. Reduced ubiquitination was also observed for an inactive mutated form of the molecule (M1WI), suggesting that MARCH1 is capable of autoubiquitination. Immunoprecipitation and energy transfer experiments demonstrated that MARCH1 homodimerizes and also forms heterodimers with others family members. Coexpression of MARCH1 decreased the protein levels of the inactive M1WI, suggesting a transubiquitination process. Taken together, our results suggest that MARCH1 may regulate its own expression through dimerization and autoubiquitination.

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“…Similarly, recent work showed that polyubiquitin chains linked to a substrates cysteine are necessary for cargo translocation across the peroxisomal membranes [25][26][27] or can be formed during the process of chain-assembly for the formation of polyubiquitin chains [28][29][30]. Other groups reported the occasional modification of threonines and serine hydroxyl groups by polyubiquitin chains [29,31].…”

Section: Ubiquitin Signalsmentioning

confidence: 91%

“…Other groups reported the occasional modification of threonines and serine hydroxyl groups by polyubiquitin chains [29,31]. Ubiquitination on serine, threonine and cysteine has to be analyzed with modified proteomic methods because of the chemical nature of the ester linkage, which is subject to hydrolysis during the typical workflow of a proteomic experiment.…”

Section: Ubiquitin Signalsmentioning

confidence: 99%