Enhancement of TGF-β Signaling Responses by the E3 Ubiquitin Ligase Arkadia Provides Tumor Suppression in Colorectal Cancer

Sharma, Vikas; Antonacopoulou, Anna G.; Tanaka, Shinya; Πανουτσόπουλος, Αλέξιος; Bravou, Vasiliki; Kalofonos, Haralabos P.; Episkopou, Vasso

doi:10.1158/0008-5472.can-11-1645

Cited by 37 publications

(44 citation statements)

References 39 publications

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“…Polysumoylation appears to be specifically induced by different cellular stresses which are known to generate multiple alterations that affect genome integrity, thereby perturbing cell homeostasis. Interestingly, this could provide an additional antitumor function for Arkadia, besides its tumor suppressor role described in TGF-␤ signaling (48). In mammalian cells, heat shock induces changes in the polysumoylation state of more than 300 proteins (10,11), which may thus constitute as many new potential targets for Arkadia.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple rounds of this reaction can also lead to polyubiquitination of the substrate, since ubiquitin contains many lysine residues (Lys residues 11,29,33,48, and 63) that can be targeted for subsequent attachment of ubiquitin. The most well characterized functional consequence of polyubiquitination is the proteasome-dependent degradation of substrates modified by ubiquitin chains linked through lysine 48.…”

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confidence: 99%

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Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation

Erker

Neyret‐Kahn

Seeler

et al. 2013

Molecular and Cellular Biology

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bArkadia is a RING domain E3 ubiquitin ligase that activates the transforming growth factor ␤ (TGF-␤) pathway by inducing degradation of the inhibitor SnoN/Ski. Here we show that Arkadia contains three successive SUMO-interacting motifs (SIMs) that mediate noncovalent interaction with poly-SUMO2. We identify the third SIM (VVDL) of Arkadia to be the most relevant one in this interaction. Furthermore, we provide evidence that Arkadia can function as a SUMO-targeted ubiquitin ligase (STUBL) by ubiquitinating SUMO chains. While the SIMs of Arkadia are not essential for SnoN/Ski degradation in response to TGF-␤, we show that they are necessary for the interaction of Arkadia with polysumoylated PML in response to arsenic and its concomitant accumulation into PML nuclear bodies. Moreover, Arkadia depletion leads to accumulation of polysumoylated PML in response to arsenic, highlighting a requirement of Arkadia for arsenic-induced degradation of polysumoylated PML. Interestingly, Arkadia homodimerizes but does not heterodimerize with RNF4, the other STUBL involved in PML degradation, suggesting that these two E3 ligases do not act synergistically but most probably act independently during this process. Altogether, these results identify Arkadia to be a novel STUBL that can trigger degradation of signal-induced polysumoylated proteins.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Arkadia, a Novel SUMO-Targeted Ubiquitin Ligase Involved in PML Degradation

Erker

Neyret‐Kahn

Seeler

et al. 2013

Molecular and Cellular Biology

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“…RASA1 helps in control of cellular proliferation and its mutation is associated with basal cell carcinoma [35]. RNF111 acts as a tumour suppressor in preventing development and progression of colorectal cancer [36]. CDCA7L interacts with c-Myc in bringing about cellular transformation in medulloblastoma [37].…”

Section: Discussionmentioning

confidence: 99%

Somatic Variations in Cervical Cancers in Indian Patients

Das

Bansal

Rao³

et al. 2016

PLoS ONE

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There are very few reports that describe the mutational landscape of cervical cancer, one of the leading cancers in Indian women. The aim of the present study was to investigate the somatic mutations that occur in cervical cancer. Whole exome sequencing of 10 treatment naïve tumour biopsies with matched blood samples, from a cohort of Indian patients with locally advanced disease, was performed. The data revealed missense mutations across 1282 genes, out of 1831 genes harbouring somatic mutations. These missense mutations (nonsynonymous + stop-gained) when compared with pre-existing mutations in the COSMIC database showed that 272 mutations in 250 genes were already reported although from cancers other than cervical cancer. More than 1000 novel somatic variations were obtained in matched tumour samples. Pathways / genes that are frequently mutated in various other cancers were found to be mutated in cervical cancers. A significant enrichment of somatic mutations in the MAPK pathway was observed, some of which could be potentially targetable. This is the first report of whole exome sequencing of well annotated cervical cancer samples from Indian women and helps identify trends in mutation profiles that are found in an Indian cohort of cervical cancer.

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“…In fact, RNF111 functions not only as a tumor metastasis promoter in breast and lung cancer [19][20] but also as a tumor metastasis suppressor in colorectal cancer [35], suggesting that either function predominates dependent on the cell-type context. Our results showed that RNF111 exhibited a invasion-promoting role in NSCLC.…”

Section: Discussionmentioning

confidence: 99%