Protein Inhibitor of Activated STAT3 (PIAS3) Protein Promotes SUMOylation and Nuclear Sequestration of the Intracellular Domain of ErbB4 Protein

Sundvall, Maria; Korhonen, Anna; Vaparanta, Katri; Anckar, Julius; Halkilahti, Kalle; Salah, Zaidoun; Aqeilan, Rami I.; Palvimo, Jorma J.; Sistonen, Lea; Elenius, Klaus

doi:10.1074/jbc.m111.335927

Cited by 40 publications

(49 citation statements)

References 45 publications

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“…The biology of the PIAS3 protein is not fully clear. Originally described as a STAT3-specific inhibitor (38), it also blocks the microphthalmia transcription factor (39), acts as a SUMOylation cofactor for nuclear receptors, and binds to the intracellular domain of ErbB4 to enhance its nuclear retention (40). Unlike SOCS3 and PIAS3, which block the acute cytokineinduced responses, GRIM-19 blocks oncogene-induced cellular transformation and acts against chronically active STAT3 (41).…”

Section: Discussionmentioning

confidence: 99%

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Kalakonda¹,

Nallar²,

Jaber

et al. 2013

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

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Significance Gene-associated with retinoid-interferon induced mortality-19 (GRIM-19) is an interferon-retinoid–regulated growth suppressor that inhibits cell growth by targeting the transcription factor STAT3 for inhibition. In primary human tumors GRIM-19 is suppressed or mutated, leading to constitutive STAT3 activity and indicating the tumor-suppressive function of GRIM-19. To understand the in vivo role of Grim-19 in tumor development, we generated a Grim-19 conditional knockout mouse. We found that deletion of even a single Grim-19 allele is sufficient to augment skin tumorigenesis in mice, thus establishing a critical role for Grim-19 as a tumor suppressor. Tumors that developed in the absence of Grim-19 exhibited mitochondrial respiratory chain dysfunction, elevated glycolysis, and Stat3-responsive gene expression.

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Section: Discussionmentioning

confidence: 99%

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Kalakonda¹,

Nallar²,

Jaber

et al. 2013

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

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“…Furthermore, SUMO modification of these proteins at their NLS or SUMOylation of other proteins at non-NLS sites, including actin, SENP1, ErB4, and Smad4, promotes their localization to the nucleus (23)(24)(25)(26). However, it is unclear whether this is because their SUMOylation leads to nuclear localization or if SUMOylation prevents these proteins from being exported to the cytoplasm.…”

mentioning

confidence: 99%

Sumoylation of SAE2 C Terminus Regulates SAE Nuclear Localization

Truong

Lee

et al. 2012

Journal of Biological Chemistry

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Background:The mechanisms that regulate intracellular trafficking of the SUMOylation enzymes are not well understood. Results: SUMO modification of SAE2 at and near the NLS, in addition to its NLS, is required for its nuclear localization. Conclusion: A mechanism regulating SUMOylation activity in different cellular compartments was identified. Significance: This SUMOylation-dependent mechanism of regulating intracellular localization may occur widely.

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“…It has previously been shown that the IGF-1R and ErbB-4 are SUMOylated by SUMO-1 (8,23). SUMOylated proteins were initially reported to be expressed in the cell nucleus, but later also in other parts of the cell (18).…”

Section: Egfr Is Sumoylatedmentioning

confidence: 99%

“…Recently, the insulin-like growth factor 1 receptor (IGF-1R) and ErbB-4 were shown to be modified by SUMO-1 and upon SUMOylation the receptors become stabilized and translocated into the cell nucleus (8,23,24).…”

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confidence: 99%

The Nucleus-Localized Epidermal Growth Factor Receptor Is SUMOylated

et al. 2015

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The epidermal growth factor receptor (EGFR) plays important roles in normal and cancer cell growth. The EGFR has principally two different signaling pathways: the canonical kinase route induced at the plasma membrane resulting in an intracellular phosphorylation cascade via MAPKs and PI3K and the more recently discovered pathway by which the receptor functions as a transcriptional co-activator inside the cell nucleus. Full length EGFR translocates to the inner nuclear membrane, via the endoplasmic reticulum, through association with the sec61β translocon. The c-myc (MYC) and cyclin D1 (CNND1) genes represent two target genes for nuclear EGFR (nEGFR). Here we show that EGFR is SUMOylated and that the SUMO-1-modified receptors are almost unexceptionally nuclear. Co-immunoprecipitation experiments suggest that EGFR is multi-SUMOylated. Using two mass spectrometry-based strategies (matrix-assisted laser desorption ionization time of flight and electrospray ionization liquid chromatography with tandem mass spectrometry), lysine 37 was identified as a SUMO-1-modified residue by both methods. A lysine 37 site mutant (K37R) was transfected into EGFR deficient cells. Total SUMOylation of EGFR was not altered in the K37R-transfected cells, confirming the presence of other SUMOylation sites. To gain preliminary insight into the possible functional role of EGFR SUMOylation, we compared the effect of expression of the wild-type EGFR with the K37R mutant on promoter activity and expression of CMYC and CNND1. Our results indicate that SUMO-1 modification may affect the transcriptional activity of EGFR, which might have additional impact on, e.g., cancer progression.

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Protein Inhibitor of Activated STAT3 (PIAS3) Protein Promotes SUMOylation and Nuclear Sequestration of the Intracellular Domain of ErbB4 Protein

Cited by 40 publications

References 45 publications

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Sumoylation of SAE2 C Terminus Regulates SAE Nuclear Localization

The Nucleus-Localized Epidermal Growth Factor Receptor Is SUMOylated

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