Degradation of Activated K-Ras Orthologue via K-Ras-specific Lysine Residues Is Required for Cytokinesis

Sumita, Kazutaka; Yoshino, Hirofumi; Sasaki, Mika; Majd, Nazanin; Kahoud, Emily Rose; Takahashi, Hidenori; Takeuchi, Koh; Kuroda, Taruho S.; Lee, Susan; Charest, Pascale G.; Takeda, Kosuke; Asara, John M.; Firtel, Richard A.; Anastasiou, Dimitrios; Sasaki, Atsuo T.

doi:10.1074/jbc.m113.531178

Cited by 9 publications

(5 citation statements)

References 53 publications

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“…Finally, additional posttranslational modifications of Ras that modulate Ras function include mono-ubiquitination of H-Ras 81 and of K-Ras 82 , polyubiquitination of K-Ras 83 and acetylation of K-Ras4B 84 . However, the enzymology of these modifications, the significance of their low stoichiometry, and their potential value as therapeutic targets remain unresolved.…”

Section: Inhibitors Of Membrane Association/subcellular Localization mentioning

confidence: 99%

Drugging the undruggable RAS: Mission Possible?

Cox

Fesik

Kimmelman

et al. 2014

Nat Rev Drug Discov

1,601

1,774

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Despite more than three decades of intensive effort, no effective pharmacologic inhibitors of the Ras oncoproteins have reached the clinic, prompting the widely held perception that Ras proteins are “undruggable”. However, there is renewed hope that this is not the case. In this review, we summarize the progress and promise of five key directions. First, we focus on the prospects of direct inhibitors of Ras. Second, we revisit the issue of whether blocking Ras membrane association is a viable approach. Third, we assess the status of targeting Ras downstream effector signalling, arguably the most favourable current direction. Fourth, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, Ras-mediated changes in cell metabolism have recently been described. Can these changes be exploited for new therapeutic directions? We conclude with perspectives on how additional complexities, not yet fully understood, may impact each of these approaches.

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Section: Inhibitors Of Membrane Association/subcellular Localization mentioning

confidence: 99%

Drugging the undruggable RAS: Mission Possible?

Cox

Fesik

Kimmelman

et al. 2014

Nat Rev Drug Discov

1,601

1,774

View full text Add to dashboard Cite

show abstract

“…This also allowed us to combine the use of the reporter cell line with automated flow cytometry, which significantly improved our throughput. It is noteworthy that the KRAS G12C reporter construct needs to encompass the full-length protein sequence, including the C-terminal stretch, which is reported to bear the ubiquitination sites of the protein (Sumita et al, 2014). In addition, tagging the GFP on the N terminus of KRAS G12C rather than C terminus preserves the CAAX motif on the C terminus of KRAS, which may affect plasma membrane targeting.…”

Section: Evaluating the Degrader Compounds In Gfp-kras G12c Reporter Cellsmentioning

confidence: 99%

Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

Zeng

Xiong

Safaee

et al. 2020

Cell Chemical Biology

208

194

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“…Consistent with this observation, the accumulation of proximal lysines is preferentially targeted by UBQ [ 41 ]. Notably, no single K ubiquitination, but rather the entire C-terminal cluster of ubiquitinated lysine residues, is important for the biological behavior of the Neuronal Glycine Transporter [ 42 , 43 ]. A K residue cluster has also been identified in the major UBQ acceptor site of Arn1p, a ferrichrome transporter in Saccharomyces cerevisiae [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

The Ubiquitination of the Influenza A Virus PB1-F2 Protein Is Crucial for Its Biological Function

et al. 2015

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The aim of the present study was to identify what influences the short half-life of the influenza A virus PB1-F2 protein and whether a prolonged half-life affects the properties of this molecule. We hypothesized that the short half-life of PB1-F2 could conceal the phenotype of the protein. Because proteasome degradation might be involved in PB1-F2 degradation, we focused on ubiquitination, a common label for proteasome targeting. A cluster of lysine residues was demonstrated as an ubiquitination acceptor site in evolutionary and functionally distinct proteins. The PB1-F2 sequence alignment revealed a cluster of lysines on the carboxy terminal end of PB1-F2 in almost all of the GenBank sequences available to date. Using a proximity ligation assay, we identified ubiquitination as a novel posttranslational modification of PB1-F2. Changing the lysines at positions 73, 78, and 85 to arginines suppressed the ubiquitination of A/Puerto Rico/8/1934 (H1N1)-derived PB1-F2. The mutation of the C-terminal lysine residue cluster positively affected the overall expression levels of avian A/Honk Kong/156/1997 (H5N1)- and mammalian A/Puerto Rico/8/1934 (H1N1)-derived PB1-F2. Moreover, increased PB1-F2 copy numbers strengthened the functions of this virus in the infected cells. The results of a minigenome luciferase reporter assay revealed an enhancement of viral RNA-dependent RNA polymerase activity in the presence of stabilized PB1-F2, regardless of viral origin. IFNβ antagonism was enhanced in 293T cells transfected with a plasmid expressing stabilized K→R mutant variants of PB1-F2. Compared with PB1-F2 wt, the loss of ubiquitination enhanced the antibody response after DNA vaccination. In summary, we revealed that PB1-F2 is an ubiquitinated IAV protein, and this posttranslational modification plays a central role in the regulation of the biological functions of this protein.

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Degradation of Activated K-Ras Orthologue via K-Ras-specific Lysine Residues Is Required for Cytokinesis

Cited by 9 publications

References 53 publications

Drugging the undruggable RAS: Mission Possible?

Drugging the undruggable RAS: Mission Possible?

Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

The Ubiquitination of the Influenza A Virus PB1-F2 Protein Is Crucial for Its Biological Function

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