HECT Domain-containing E3 Ubiquitin Ligase Nedd4 Interacts with and Ubiquitinates Sprouty2

Edwin, Francis; Anderson, Kathryn B.; Patel, Tarun B.

doi:10.1074/jbc.m109.030882

Cited by 42 publications

(43 citation statements)

References 64 publications

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“…At this time, however, we cannot rule out the possibility that our observations may also be partly due to the effect of Mnk activities on other known substrates such as Sprouty2, cPLA2, and hnRNPA1 (22)(23)(24)(25). These substrates are reportedly involved in cell growth or tumorigenesis (45)(46)(47)(48), but the in vivo significance of their phosphorylated forms has yet to be proven.…”

Section: Discussionmentioning

confidence: 92%

Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Ueda

Sato

Elia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

189

196

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MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) are proteinserine/threonine kinases that are activated by ERK or p38 and phosphorylate eIF4E, which is involved in cap-dependent translation initiation. However, Mnk1/2 double knockout (Mnk-DKO) mice show normal cell growth and development despite an absence of eIF4E phosphorylation. Here we show that the tumorigenesis occurring in the Lck-Pten mouse model (referred to here as tPten −/− mice) can be suppressed by the loss of Mnk1/2. Phosphorylation of eIF4E was greatly enhanced in lymphomas of parental tPten −/− mice compared with lymphoid tissues of wild-type mice, but was totally absent in lymphomas of tPten −/− ; Mnk-DKO mice. Notably, stable knockdown of Mnk1 in the human glioma cell line U87MG resulted in dramatically decreased tumor formation when these cells were injected into athymic nude mice. Our data demonstrate an oncogenic role for Mnk1/2 in tumor development, and highlight these molecules as potential anticancer drug targets that could be inactivated with minimal side effects.

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Section: Discussionmentioning

confidence: 92%

Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Ueda

Sato

Elia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

189

196

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“…Different cell types express different amounts of Spry2 and different amounts of post-translationally modified Spry2. As mentioned above, Spry2 migrates as a doublet representing its phosphorylated and dephosphorylated forms (29,50), and thus, it would appear that in A549 cells a larger amount of Spry2 is phosphorylated, whereas in Hep3B cells a larger amount of dephosphorylated Spry2 is present (Fig. 2B).…”

Section: Endogenous Spry2 Regulates Hif1␣ and Hif2␣ Proteinmentioning

confidence: 99%

“…pCMV-3ϫ-FLAG-ubiquitin was kindly provided by Dr. Adriano Marchese, Medical College of Wisconsin. The cloning of FLAG-Spry2 was described previously (29). FLAG-Spry1, FLAG-Spry3, and FLAG-Spry4 were generous gifts from Dr. Graeme Guy, Institute of Molecular and Cell Biology, Singapore.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, a number of studies have investigated mechanisms that regulate the expression of Spry2, as well as how Spry2 modulates signaling via receptor tyrosine kinases (20 -25). At the posttranslational level, Spry2 has been shown to be ubiquitylated and targeted for proteosomal degradation by c-Cbl (26,27), Siah2 (28), Nedd4-1 (29), and pVHL with its associated E3 ligase (30). Interestingly, in some patient-derived hepatocellular carcinomas, when Spry2 levels were decreased, the levels of Nedd4-1 were elevated (8).…”

mentioning

confidence: 99%

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Sprouty2 Protein Regulates Hypoxia-inducible Factor-α (HIFα) Protein Levels and Transcription of HIFα-responsive Genes

Hicks

Patel

2016

Journal of Biological Chemistry

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The ␣-subunits of hypoxia-inducible factors (HIF1␣ and HIF2␣) promote transcription of genes that regulate glycolysis and cell survival and growth. Sprouty2 (Spry2) is a modulator of receptor tyrosine kinase signaling and inhibits cell proliferation by a number of different mechanisms. Because of the seemingly opposite actions of HIF␣ subunits and Spry2 on cellular processes, we investigated whether Spry2 regulates the levels of HIF1␣ and HIF2␣ proteins. In cell lines from different types of tumors in which the decreased protein levels of Spry2 have been associated with poor prognosis, silencing of Spry2 elevated HIF1␣ protein levels. Increases in HIF1␣ and HIF2␣ protein levels due to silencing of Spry2 also up-regulated HIF␣ target genes. Using HIF1␣ as a prototype, we show that Spry2 decreases HIF1␣ stability and enhances the ubiquitylation of HIF1␣ by a von Hippel-Lindau protein (pVHL)-dependent mechanism. Spry2 also exists in a complex with HIF1␣. Because Spry2 can also associate with pVHL, using a mutant form of Spry2 (3P/3A-Spry2) that binds HIF1␣, but not pVHL, we show that WT-Spry2, but not the 3P/3A-Spry2 decreases HIF1␣ protein levels. In accordance, expression of WT-Spry2, but not 3P/3A-Spry2 results in a decrease in HIF1␣-sensitive glucose uptake. Together our data suggest that Spry2 acts as a scaffold to bring more pVHL/associated E3 ligase in proximity of HIF1␣ and increase its ubiquitylation and degradation. This represents a novel action for Spry2 in modulating biological processes regulated by HIF␣ subunits.The four Sprouty proteins (Spry1 to Spry4), which are products of different genes, regulate downstream signaling from certain receptor tyrosine kinases and therefore play a major role in development (1-5). Because cell proliferation processes in normal development and tumor growth overlap, some of the Spry 2 proteins, such as Spry1, Spry2, and Spry4, also regulate tumor growth (6 -16). Among the four isoforms, Spry2 is ubiquitously expressed and well studied in cancer. In cancers of the liver, lung, breast, and prostate, Spry2 levels are decreased (6 -11, 17-19). The decrease in Spry2 levels in these cancers has been correlated to poor patient prognosis and shorter survival of patients implicating Spry2 as a tumor suppressor. Therefore, a number of studies have investigated mechanisms that regulate the expression of Spry2, as well as how Spry2 modulates signaling via receptor tyrosine kinases (20 -25). At the posttranslational level, Spry2 has been shown to be ubiquitylated and targeted for proteosomal degradation by c-Cbl (26, 27), Siah2 (28), Nedd4-1 (29), and pVHL with its associated E3 ligase (30). Interestingly, in some patient-derived hepatocellular carcinomas, when Spry2 levels were decreased, the levels of Nedd4-1 were elevated (8).It is now well established that as tumors proliferate rapidly prior to angiogenesis, the oxygen from the nearby vasculature cannot diffuse throughout the entire tumor resulting in the formation of a hypoxic environment (31). Cells adapt to the hypoxic envir...

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“…11 Phosphorylation of serines 112/121 is crucial for the inhibitory interaction with BRAF kinase 12 and to modulate protein degradation by NEDD4. 13 The p.(Arg119Trp) variant was run on NetPhos2.0 software to evaluate the phosphorylation score of different serines around the Arg119Trp variant and the results showed that the presence of tryptophan lowered the phosphorylation score of serine 121 from 0.996 to 0.602 (Figure 2a), suggesting that this variant, in addition to changing a highly conserved amino-acid residue has also an impact on the consensus sequence of the kinase phosphorylating SPRY2 at position 121.…”

Section: Exome Sequencing and Bioinformatics Analysismentioning

confidence: 99%

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

Milillo¹,

Carpia²,

Costanzi

et al. 2015

Eur J Hum Genet

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IgA nephropathy (IgAN) represents the most common primary glomerulonephritis worldwide with a prevalence of 25-50% among patients with primary glomerulopathies. In~5-10% of the patients the disease segregates with an autosomal dominant (AD) pattern. Association studies identified loci on chromosomes 1q32, 6p21, 8p23, 17p13, 22q12, whereas classical linkage studies on AD families identified loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22. We have studied a large Sicilian family where IgAN segregates with an AD transmission. To identify the causal gene, the exomes of two affected and one unaffected individual have been sequenced. From the bioinformatics analysis a p.(Arg119Trp) variant in the SPRY2 gene was identified as the probable disease-causing mutation. Moreover, functional characterization of this variant showed that it is responsible for the inhibition of the MAPK/ERK1/2 pathway. The same effect was observed in two sporadic IgAN patients carriers of wild-type SPRY2, suggesting that downregulation of the MAPK/ERK1/2 pathway represents a common mechanism leading to IgAN.

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HECT Domain-containing E3 Ubiquitin Ligase Nedd4 Interacts with and Ubiquitinates Sprouty2

Cited by 42 publications

References 64 publications

Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Sprouty2 Protein Regulates Hypoxia-inducible Factor-α (HIFα) Protein Levels and Transcription of HIFα-responsive Genes

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

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