Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction

Gao, Daming; Inuzuka, Hiroyuki; Tseng, Alan; Chin, Y. Rebecca; Toker, Alex; Wei, Wenyi

doi:10.1038/ncb1847

Cited by 227 publications

(261 citation statements)

References 49 publications

Supporting

Mentioning

239

Contrasting

Order By: Relevance

“…Consistently, we did not observe significant changes in the mRNA levels of Cdh1 ( Figure 3A) or the APC Cdh1 substrates Cdc20 ( Figure 3B) and Skp2 ( Figure 3C) in Fbw7 −/− DLD1 cells compared with the WT DLD1 cells. On the other hand, using either Cycloheximide [41,42] or Anisomycin [43] to block protein synthesis as a means to measure protein stability, we Figure S3A, and S3D-S3H). These results indicate that increased protein stability, but not changes in mRNA levels, contributes to the elevated expression of various APC Cdh1 substrates in Fbw7 −/− cells.…”

Section: Fbw7 Regulates the Stability Of Various Apc Cdh1 Substratesmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

et al. 2013

Self Cite

View full text Add to dashboard Cite

Fbw7 and Cdh1 are substrate-recognition subunits of the SCF-and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCF Fbw7 substrates, including cyclin E, but also have increased expression of various APC Cdh1 substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APC Cdh1 activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APC Cdh1 substrates to levels comparable to those in wildtype (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APC Cdh1 substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APC Cdh1 substrates in Fbw7-deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCF Fbw7 and APC Cdh1 substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors.

show abstract

Section: Fbw7 Regulates the Stability Of Various Apc Cdh1 Substratesmentioning

confidence: 99%

“…Cell culture and cell synchronization experiments were performed as previously described [41,50]. Lentiviral shRNA packaging and infection were also performed as previously described [51].…”

Section: Cell Culture and Cell Synchronizationmentioning

confidence: 99%

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…In liver cancer, the phosphorylation of AKT is remarkably intensified; therefore, AKT has become an important target of anti-cancer research (Yap et al, 2008). Studies on breast cancer and prostate cancer suggested that PI3K/AKT could increase the expression of S-phase kinase-associated protein 2 (Skp2) at different levels, transcription, translation, and post-translation, to promote the occurrence of tumors (Gao et al, 2009;Lin et al, 2009;Li et al, 2013). In this study, the expression of PI3K and AKT in colorectal cancer was significantly higher than those in tumor-adjacent tissues, and was closely correlated with the differentiation level of colorectal cancer ( Li et al.…”

Section: Discussionmentioning

confidence: 99%

Expression of Ang-2/Tie-2 and PI3K/AKT in Colorectal Cancer

Zhang

Wang²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

“…One of the most significant extensions to our understanding of isoform-specific Akt signaling was the identification of Skp2 as a direct target of Akt1 (33,34). The Akt1-mediated phosphorylation of Skp2, a component of the SCF complex E3 ligase, ensures cell cycle progression by degradation of p27, a potent inhibitor of Cdks.…”

Section: Isoform-specific Signaling To Downstream Substratesmentioning

confidence: 99%

The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

Santi¹,

Douglas²,

Lee³

2010

BioMolecular Concepts

View full text Add to dashboard Cite

Akt (also known as protein kinase B or PKB) is the major downstream nodal point of the PI3K signaling pathway. This pathway is a promising anticancer therapeutic target, because constitutive activation of the PI3K-Akt pathway is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies. The Akt serine/threonine kinase regulates diverse cellular functions including cell growth, proliferation, glucose metabolism, and survival. Although all three known Akt isoforms (Akt1-3) are encoded by separate genes, their amino acid sequences show a high degree of similarity. For this and other reasons, it has long been assumed that all three Akt isoforms are activated in the same way, and their functions largely overlap. However, accumulating lines of evidence now suggest that the three Akt isoforms might have unique modes of activation and many distinct functions. In particular, it has recently been found that the Akt isoforms are localized at different subcellular compartments in both adipocytes and cancer cells. In this review, we highlight the unique roles of each Akt isoform by introducing published data obtained from both in vitro and in vivo studies. We also discuss the significant potential of the Akt isoforms as effective anticancer therapeutic targets.

show abstract

Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction

Cited by 227 publications

References 49 publications

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

Expression of Ang-2/Tie-2 and PI3K/AKT in Colorectal Cancer

The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

Contact Info

Product

Resources

About