The regulatory roles of phosphatases in cancer

Stebbing, Justin; Lit, Lei Cheng; Zhang, H; Darrington, R. Siobhan; Melaiu, Ombretta; Rudraraju, Bharath; Giamas, Georgios

doi:10.1038/onc.2013.80

Cited by 89 publications

(77 citation statements)

References 253 publications

(115 reference statements)

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“…The suppressor gene PTEN is one of the most commonly mutated genes in human cancers (47,53). It is both a lipid phosphatase that eliminates phosphatidylinositol 3,4,5-trisphosphate generated by PI3K and a protein phosphatase which self-dephosphorylates at Thr 366 , and both activities appear to be relevant in invasion (57).…”

Section: Innovationmentioning

confidence: 99%

The PTEN/NRF2 Axis Promotes Human Carcinogenesis

Rojo

Rada

Mendiola

et al. 2014

Antioxidants & Redox Signaling

109

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Aims: A recent study conducted in mice reported that liver-specific knockout of tumor suppressor Pten augments nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional activity. Here, we further investigated how phosphatase and tensin homolog deleted on chromosome 10 (PTEN) controls NRF2 and the relevance of this pathway in human carcin ogenesis. Results: Drug and genetic targeting to PTEN and phosphoproteomics approaches indicated that PTEN leads to glycogen synthase kinase-3 (GSK-3)-mediated phosphorylation of NRF2 at residues Ser 335 and Ser 338 and subsequent beta-transducin repeat containing protein (b-TrCP)-dependent but Kelch-like ECH-associated protein 1 (KEAP1)-independent degradation. Rescue experiments in PTEN-deficient cells and xerographs in athymic mice indicated that loss of PTEN leads to increased NRF2 signature which provides a proliferating and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1). Innovation: These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3/b-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas. Conclusion: Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target. Antioxid. Redox Signal. 21, 2498-2514.

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Section: Innovationmentioning

confidence: 99%

The PTEN/NRF2 Axis Promotes Human Carcinogenesis

Rojo

Rada

Mendiola

et al. 2014

Antioxidants & Redox Signaling

109

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“…21 The presence of phosphatase activity in various tissues and their upregulated expression in certain types of cancer might provide a solution for a broader clinical application of 5-ALA PDT and PD. [22][23][24][25] Phospho-self-immolative 5-ALA (PSI-ALA-Hex) and phospho-5-ALA (P-ALA-Hex) keep the lipophilicity of ALA-Hex which facilitates their uptake into cells compared to 5-ALA while having reduced acute toxicity and improved stability over a wide range of pH values. In addition, their activation and conversion to 5-ALA is controlled and can be tailored with changes to chemical structure ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Activity of phosphatase-sensitive 5-aminolevulinic acid prodrugs in cancer cell lines

Herceg

Lange

Allémann

et al. 2017

Journal of Photochemistry and Photobiology B: Biology

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“…The protein tyrosine phosphatase (PTP) family plays an important part in the inhibition or control of growth, and members may exert oncogenic functions (31). Several studies have detected aberrant DNA methylation of the PTPN6 gene in gastric cancer (32,33). TGFBR2 , a constitutively active kinase, is reported to play a tumor suppressor role in the TGFβ pathway in gastric cancer (34).…”

Section: Discussionmentioning

confidence: 99%

Transduction motif analysis of gastric cancer based on a human signaling network

Liu¹,

Li²,

Jiang³

et al. 2014

Braz J Med Biol Res

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To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR, MAPK14, BCL2L1, KRT18, PTPN6, CASP3, TGFBR2, AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.

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The regulatory roles of phosphatases in cancer

Cited by 89 publications

References 253 publications

The PTEN/NRF2 Axis Promotes Human Carcinogenesis

The PTEN/NRF2 Axis Promotes Human Carcinogenesis

Activity of phosphatase-sensitive 5-aminolevulinic acid prodrugs in cancer cell lines

Transduction motif analysis of gastric cancer based on a human signaling network

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