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USP2 binds SKP2. 36 / 36
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"However, USP2 can interact with NBS1 protein when both proteins are overexpressed (Fig. 2C), and direct interaction between USP2 and SKP2 was also observed in a previous study (42)."
36436562
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"In this study, we verified that the natural product Tan IIA markedly reduced the phosphorylation and total protein level of Skp2 by disrupting the interaction between Skp2 and USP2, resulting in increased Skp2 K48-linked ubiquitination and degradation."
41051621
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"It has been reported that E2F4 binds directly with USP2 (ubiquitin specific peptidase 2) in gastric cancer cells [29], while USP2 could bind with SKP2 and USP2-stabilized SKP2 did not destabilize its substrate P21 [30]."
38980592
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"We first screened a panel of DUBs and found that both USP2 and USP21 bound to endogenous SKP2, but only USP2 deubiquitylated and stabilized SKP2 protein."
34425107
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"Mechanistically, USP2 bound to SKP2 via the leucine-rich repeat substrate-binding domain on SKP2 to disrupt the SKP2-substrate binding, leading to stabilization of both SKP2 and these substrates."
34425107
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"In this study, we investigated a panel of DUBs for their potential binding of endogenous SKP2 by a conventional pull-down assay and found that both USP2 and USP21 bind to SKP2, but only USP2 stabilized SKP2."
34425107
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"USP2 bound to and stabilized SKP2."
34425107
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"Among the 9 DUBs, USP2 and USP21 selectively bound to SKP2 (Fig. 1A)."
34425107
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"Collectively, these results showed that USP2 interacts and stabilizes SKP2."
34425107
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"In this study, we showed that USP2 is a new bona fide deubiquitylase of SKP2, which is supported by the following lines of evidence: (1) SKP2 binding with USP2 under physiological conditions; (2) the levels of endogenous SKP2 are directly regulated by USP2 manipulation with USP2 knockdown to decrease and USP2 overexpression to increase SKP2; (3) USP2 stabilized SKP2 by cleaving SKP2 polyubiquitylation chains to extend SKP2 half-life; (4) pharmacologic inhibition of USP2 significantly impaired SKP2 stability; and (5) USP2 catalytic-inactive mutant USP2–C276A had no effect on SKP2."
34425107
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"Our study fits the following working model that USP2 has a dual role in stabilizing both SKP2 and SKP2 substrate through binding to the LRR domain on SKP2: (a) when SKP2 is free of USP2 binding, it promotes the degradation of p21 and p27, and (b) when SKP2 binds to USP2, p21 and p27 are freed up and stabilized (Fig. 6E)."
34425107
sparser
"Mechanistically, USP2 bound to SKP2 via the leucine-rich repeat substrate-binding domain on SKP2 to disrupt the SKP2-substrate binding, leading to stabilization of both SKP2 and these substrates."
34425107
sparser
"Specifically, Tan IIA induces ubiquitination-mediated Skp2 degradation by attenuating the interaction between USP2 and Skp2."
41051621
sparser
"Our study revealed a new mechanism of the cross-talk among the E3–DUB substrates and its potential implication in targeting the USP2–SKP2 axis for cancer therapy."
34425107
biogrid
No evidence text available
34425107
biogrid
No evidence text available
34425107
sparser
"Mechanistically, USP2 interacts with SKP2 and stabilizes its expression to promote lung cancer progression."
37594087
sparser
"This is due to USP2 binding to SKP2 via the leucine-rich repeat (LRR) domain on SKP2, the domain that mediates SKP2 substrate binding."
34425107
sparser
"The results showed that USP2 binds with Skp2 in CRC cells, and this interaction was attenuated by Tan IIA induction."
41051621
sparser
"In this study, we showed that USP2 is a new bona fide deubiquitylase of SKP2, which is supported by the following lines of evidence: (1) SKP2 binding with USP2 under physiological conditions; (2) the levels of endogenous SKP2 are directly regulated by USP2 manipulation with USP2 knockdown to decrease and USP2 overexpression to increase SKP2; (3) USP2 stabilized SKP2 by cleaving SKP2 polyubiquitylation chains to extend SKP2 half-life; (4) pharmacologic inhibition of USP2 significantly impaired SKP2 stability; and (5) USP2 catalytic-inactive mutant USP2–C276A had no effect on SKP2."
34425107
sparser
"It has been reported that E2F4 binds directly with USP2 (ubiquitin specific peptidase 2) in gastric cancer cells [ xref ], while USP2 could bind with SKP2 and USP2-stabilized SKP2 did not destabilize its substrate P21 [ xref ]."
38980592
sparser
"The USP2–SKP2 binding disrupts the SKP2 substrate binding."
34425107
sparser
"USP2 bound to and stabilized SKP2."
34425107
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"We further confirmed that ectopic expression of WT USP2, but not of its catalytic-inactive mutant USP2–C276A, caused accumulation of endogenous SKP2 in a dose-dependent manner ( xref D ), and endogenous USP2 and SKP2 bound to each other under a physiological condition detected in a reciprocal immunoprecipitation (IP) assay ( xref E )."
34425107
sparser
"USP2 interacts with SKP2 via the LRR domain of SKP2 to disrupt the SKP2 substrate binding."
34425107
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"We first confirmed that USP2 did not directly bind to SKP2 substrates, excluding the possibility that USP2 stabilizes SKP2 substrates by directly deubiquitylating them ( xref A )."
34425107
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"The rationale for this combination therapy stems from our mechanistic insights: Tan IIA disrupts the USP2-Skp2 interaction to promote Skp2 degradation, while ML364 directly inhibits USP2’s deubiquitinase activity that is critical for Skp2 stabilization."
41051621
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"The binding between USP2 and Skp2 disrupts the Skp2-substrate binding, and stabilizes both Skp2 and substrates (Zhang et al., 2021)."
37089937
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"However, USP2 can interact with NBS1 protein when both proteins are overexpressed ( xref C ), and direct interaction between USP2 and SKP2 was also observed in a previous study ( xref )."
36436562
sparser
"We, therefore, investigated whether the SKP2–USP2 binding is also phosphorylation dependent."
34425107
sparser
"We treated cell lysates with λPPase and found a significant attenuation of the SKP2 substrate binding, as expected, but without much affecting the SKP2–USP2 binding ( xref F )."
34425107
sparser
"Thus, the SKP2–USP2 binding appears to be phosphorylation independent."
34425107
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"Finally, we determined the biological significance of the USP2–SKP2 interaction."
34425107
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"We hypothesize that their combined action may dually target the USP2-Skp2 axis, resulting in synergistic enhancement of Skp2 degradation and consequently more potent suppression of the Skp2/Akt/HK2-mediated glycolytic pathway and 5-Fu resistance."
41051621
sparser
"We reasoned that while ML364 inactivated USP2 catalytic activity, this small molecule is unlikely to disrupt the USP2–SKP2 binding, leading to less “free” SKP2 to degrade its substrates."
34425107
sparser
"Consistent with our in vitro findings, these in vivo results further confirm that the USP2-Skp2 axis plays a functional role in mediating chemoresistance, as the combined targeting of this axis by Tan IIA and ML364 achieves enhanced efficacy in overcoming 5-Fu resistance."
41051621