2016
DOI: 10.1158/0008-5472.can-15-1941
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AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation

Abstract: Epithelial-to-mesenchymal transition (EMT) is an essential physiological process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for β-TrCP-mediated Twist1 ubiqui… Show more

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Cited by 71 publications
(92 citation statements)
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“…Activation of PKB (AKT1) leads to a marked increase in Twist1 phosphorylation at Ser42 in the nucleus. Subsequent study further confirms that AKT1 physically associates with Twist1 and phosphorylation of Twist1 by AKT1 is required for Twist1 ubiquitination and degradation [60]. While AKT2 primarily phosphorylates Twist1 at Ser42, AKT1 phosphorylates Twist1 at Ser42 and Thr121 in vitro and at Ser42 in vivo [61].…”
Section: Upstream Regulators Modulating Twist1 From the Transcriptionmentioning
confidence: 84%
“…Activation of PKB (AKT1) leads to a marked increase in Twist1 phosphorylation at Ser42 in the nucleus. Subsequent study further confirms that AKT1 physically associates with Twist1 and phosphorylation of Twist1 by AKT1 is required for Twist1 ubiquitination and degradation [60]. While AKT2 primarily phosphorylates Twist1 at Ser42, AKT1 phosphorylates Twist1 at Ser42 and Thr121 in vitro and at Ser42 in vivo [61].…”
Section: Upstream Regulators Modulating Twist1 From the Transcriptionmentioning
confidence: 84%
“…Remarkably, Vav1 levels significantly influence the follow‐up of patients with low p‐Akt in their primary tumors, in which low expression of Vav1 is associated with the highest probability of distant relapses. These results may be explained considering that Akt1, the only Akt isoform activated by low Vav1 in cell lines with different phenotypes, may inhibit EMT (Li et al ., ) and acts as an invasion suppressor (Riggio et al ., ). Accordingly, p‐Akt low tumors, lacking these protective mechanisms, show the greatest dependence on Vav1 levels that we demonstrated to inversely correlate with the expression of EMT‐related genes (Grassilli et al ., ).…”
Section: Discussionmentioning
confidence: 97%
“…Epidemiological and preclinical studies confirmed that activation of Akt is implicated in the pathogenesis of breast cancer also by conferring resistance to systemic treatments (Yang et al, 2016) and a number of molecules have been generated to selectively or nonselectively inhibit the three isoforms (Dey et al, 2017;Mundi et al, 2016). Therefore, despite a promising chance, emerging data revealing different or even opposite functional roles of Akt isoforms in the regulation of proliferation, migration, and invasion (Dillon et al, 2009;Li et al, 2016;Riggio et al, 2017) opened the issue of the reliability of the use of pan or isoform-specific Akt inhibitors in the different tumor subtypes and of the combined use of inhibitors and cytotoxic chemotherapy. The development of Akt inhibitors is particularly problematic in triple-negative breast cancers (TNBC) that express all three Akt isoforms and show the highest activation of the Akt downstream pathways (Chin et al, 2014;Grottke et al, 2016;Massihnia et al, 2016).…”
Section: Introductionmentioning
confidence: 99%
“…Previous publications have reported that several kinases including MAPK, AKT, GSK3β and IKKβ can phosphorylate Twist (Hong et al, 2011; Lander et al, 2013; Li et al, 2016; Zhong et al, 2013). Twist phosphorylation by MAPK, AKT, GSK3 and IKKβ reduces Twist protein expression via recruiting FBXL14/Ppa and/or β-TRCP E3 ligases, which target Twist for K48- linked ubiquitination and subsequent proteasomal degradation (Lander et al, 2011; Zhong et al, 2013).…”
Section: Discussionmentioning
confidence: 99%