Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination

Wang, Yuqi; Dohlman, Henrik G.

doi:10.1161/01.res.0000251641.57410.81

Cited by 24 publications

(26 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Posttranslational modification by ubiquitin is now appreciated for its noncanonical roles in regulating pathways other than those leading to protein degradation (15)(16)(17). In general, proteins modified with Lys-48-linked ubiquitin chains are directed to the 26S proteasomes, whereas the Lys-63 chains are suggested to play a role in endocytosis (18,19).…”

Section: Discussionmentioning

confidence: 99%

β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2

Shenoy¹,

Modi²,

Shukla

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

143

133

View full text Add to dashboard Cite

␤-Arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seventransmembrane receptors (7TMRs). Agonist-stimulated ubiquitination of ␤-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid ␤2-adrenergic receptor (␤2AR) internalization. We now report the discovery that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) binds ␤-arrestin2 and leads to the deubiquitination of ␤-arrestins. USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor ␤-arrestin complex, thus regulating the longevity and subcellular localization of receptor signalosomes. Receptors such as the ␤2AR, previously shown to form loose complexes with ␤-arrestin (''class A'') promote a ␤-arrestin conformation conducive for binding to the deubiquitinase, whereas the vasopressin V2R, which forms tight ␤-arrestin complexes (''class B''), promotes a distinct ␤-arrestin conformation that favors dissociation of the enzyme. Thus, USP33-␤-arrestin interaction is a key regulatory step in 7TMR trafficking and signal transmission from the activated receptors to downstream effectors.endocytosis ͉ G protein-coupled receptors ͉ ubiquitination ͉ phosphorylation ͉ ERK1/2

show abstract

Section: Discussionmentioning

confidence: 99%

β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2

Shenoy¹,

Modi²,

Shukla

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

143

133

View full text Add to dashboard Cite

show abstract

“…The Medusa protein-modeling suite could also be used to study the effects of protein misfolding on other signaling proteins that share high similarity between organisms. Candidates include numerous ubiquitinated signaling components in yeast and mammals (8,51,52), including G protein-coupled receptors (20 -23, 53-59) and G proteins (25, 53, 60 -63).…”

Section: Discussionmentioning

confidence: 99%

G Protein Mono-ubiquitination by the Rsp5 Ubiquitin Ligase

Torres¹,

Lee²,

Ding

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Emerging evidence suggests that ubiquitination serves as a protein trafficking signal in addition to its well characterized role in promoting protein degradation. The yeast G protein ␣ subunit Gpa1 represents a rare example of a protein that undergoes both mono-and poly-ubiquitination. Whereas mono-ubiquitinated Gpa1 is targeted to the vacuole, poly-ubiquitinated Gpa1 is directed instead to the proteasome. Here we investigate the structural requirements for mono-and poly-ubiquitination of Gpa1. We find that variants of Gpa1 engineered to be unstable are more likely to be poly-ubiquitinated and less likely to be mono-ubiquitinated. In addition, mutants that cannot be myristoylated are no longer mono-ubiquitinated but are still polyubiquitinated. Finally, we show that the ubiquitin ligase Rsp5 is necessary for Gpa1 mono-ubiquitination in vivo and that the purified enzyme is sufficient to catalyze Gpa1 mono-ubiquitination in vitro. Taken together, these data indicate that mono-and poly-ubiquitination have distinct enzyme and substrate recognition requirements; whereas poly-ubiquitination targets misfolded protein for degradation, a distinct ubiquitination apparatus targets the fully mature, fully myristoylated G protein for mono-ubiquitination and delivery to the vacuole.

show abstract

“…Earlier studies indicate that Ste4 represents a crucial component in the pathway, and its activity must be tightly regulated (30,40). Growing evidence suggests that ubiquitination is involved in the regulation of G protein signaling (17,18). Thus, we considered the possibility that Ste4 may be regulated via ubiquitination.…”

Section: Resultsmentioning

confidence: 99%

“…Evidence is emerging that ubiquitination is involved in the regulation of G protein signaling (17,18). In mammalian cells, several heterotrimeric G protein subunits, including G␣ and G␥ but not G␤, are thought to be regulated by the ubiquitination pathway (17,18).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pheromone- and RSP5-dependent Ubiquitination of the G Protein β Subunit Ste4 in Yeast

Zhu

Torres

Kelley

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Ste4 is the ␤ subunit of a heterotrimeric G protein that mediates mating responses in Saccharomyces cerevisiae. Here we show that Ste4 undergoes ubiquitination in response to pheromone stimulation. Ubiquitination of Ste4 is dependent on the E3 ligase Rsp5. Disrupting the activity of Rsp5 abolishes ubiquitination of Ste4 in vivo, and recombinant Rsp5 is capable of ubiquitinating Ste4 in vitro. We find also that Lys-340 is a major ubiquitination site on Ste4, as pheromone-induced ubiquitination of the protein is prevented when this residue is mutated to an arginine. Functionally, ubiquitination does not appear to regulate the stability of Ste4, as blocking ubiquitination has no apparent effect on either the abundance or the half-life of the protein. However, when presented with a concentration gradient of pheromone, Ste4 K340R mutant cells polarize significantly faster than wild-type cells, indicating that ubiquitination limits pheromone-directed polarized growth. Together, these findings reveal a novel stimulus-dependent posttranslational modification of a G␤ subunit, establish Ste4 as a new substrate of the E3 ligase Rsp5, and demonstrate a role for G protein ubiquitination in cell polarization.

show abstract

Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination

Cited by 24 publications

References 117 publications

β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2

β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2

G Protein Mono-ubiquitination by the Rsp5 Ubiquitin Ligase

Pheromone- and RSP5-dependent Ubiquitination of the G Protein β Subunit Ste4 in Yeast

Contact Info

Product

Resources

About