Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STAT protein

Ginger, Rebecca S.; Dalton, Emma; Ryves, W. J.; Fukuzawa, Masashi; Williams, Jeffrey; Harwood, Adrian J.

doi:10.1093/emboj/19.20.5483

Cited by 67 publications

(63 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1, C and D). Phosphorylation has been shown to regulate nuclear export of some proteins, including NF-AT (41,42). The protein conformation might be affected upon phosphorylation, and nuclear export of NF90 mediated through the NES sequence located in its N terminus could be facilitated by the conformation change.…”

Section: Discussionmentioning

confidence: 99%

“…Translocation of NF90 is mediated through an N-terminal NES, but how it is triggered is still unclear. Phosphorylation has been shown to regulate nuclear export of some proteins, including NF-AT (41,42). NF90 moves into the cytoplasmic compartment during mitosis and is highly phosphorylated (43).…”

Section: Nf90-ser 647 Phosphorylation Is Required For Its Nuclear Exportmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear Export of NF90 to Stabilize IL-2 mRNA Is Mediated by AKT-Dependent Phosphorylation at Ser647 in Response to CD28 Costimulation

Pan

Zhu²,

Dang

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

IL-2 is one of the most important cytokines required for T cell-mediated immune responses. Costimulation of CD28 in T cells up-regulates IL-2 mRNA levels via transcription activation and mRNA stabilization. Upon T cell activation, NF90, an AU-rich element (ARE)-binding protein, translocates from the nucleus into the cytoplasm, where it binds to the ARE-containing 3′ untranslated regions of IL-2 mRNA and slows down degradation of IL-2 mRNA. The translocation of NF90 is mediated through a nuclear export signal at its N terminus, but how it is triggered is still unclear. Phosphorylation of ARE-binding proteins has been reported as a signal transduction pathway to stabilize ARE-containing transcripts. In this study, we demonstrate that AKT phosphorylates NF90 on Ser647 upon CD28 costimulation. This phosphorylation is necessary for nuclear export of NF90 and IL-2 mRNA stabilization by this protein, because a mutation at Ser647 abolished both functions. We observed that treatment of cells with CD28 costimulation induced distinct increase in phosphorylation of AKT and NF90 at Ser647 concomitantly. Phosphorylation at Ser647 of NF90 up-regulated IL-2 production in response to CD28 costimulation. In vivo and in vitro data support a model in which CD28 costimulation activates AKT to phosphorylate NF90 at Ser647 and phosphorylation triggers NF90 to relocate to the cytoplasm and stabilize IL-2 mRNA.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Nf90-ser 647 Phosphorylation Is Required For Its Nuclear Exportmentioning

confidence: 99%

Nuclear Export of NF90 to Stabilize IL-2 mRNA Is Mediated by AKT-Dependent Phosphorylation at Ser647 in Response to CD28 Costimulation

Pan

Zhu²,

Dang

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Although GSK-3b is generally considered to be a cytoplasmic protein, several lines of evidence suggest that GSK-3b also functions in the nucleus and that the subcellular localization of GSK-3b is a highly dynamic process: GSK-3b was found to enter the nucleus during S phase of the cell cycle and during apoptosis (Diehl et al, 1998;Bijur and Jope, 2001) and to exit the nucleus of cardiac myocytes upon isoproterenol stimulation (Morisco et al, 2001). Nuclear GSK-3b also plays a role in controlling the nuclear/cytoplasmic distribution of several proteins such as cyclin D1, STAT, GATA-4 cmyc, NRF2, Snail and p53 (Diehl et al, 1998;Ginger et al, 2000;Morisco et al, 2001;Watcharasit et al, 2002;Gregory et al, 2003;Linseman et al, 2004;Yook et al, 2005;Salazar et al, 2006). Importantly, FRAT/ GBP, a positive regulator of b-catenin, was reported to actively export GSK-3b from the nucleus (Franca-Koh et al, 2002), and recent data show that Axin2 acts as a nucleocytoplasmic chaperone for GSK-3b (Yook et al, 2006), indicating a nuclear function for GSK-3b in the regulation of Wnt signalling.…”

Section: Discussionmentioning

confidence: 99%

Nuclear GSK-3β inhibits the canonical Wnt signalling pathway in a β-catenin phosphorylation-independent manner

et al. 2008

View full text Add to dashboard Cite

b-Catenin is the central signalling molecule of the canonical Wnt pathway, where it activates target genes in a complex with lymphoid enhancer factor/T-cell factor transcription factors in the nucleus. The regulation of b-catenin activity is thought to occur via a cytoplasmatic multiprotein complex that includes the serine/threonine kinase glycogen synthase kinase-3b (GSK-3b) that phosphorylates b-catenin, marking it for degradation by the proteasome. Here, we provide evidence showing that GSK-3b has a nuclear function in downregulating the activity of b-catenin. Using colorectal cell lines that express a mutant form of b-catenin, which cannot be phosphorylated by GSK-3b and ectopically expressed mutant b-catenin protein, we show that nuclear GSK-3b functions in a mechanism that does not involve b-catenin phosphorylation to reduce the levels of Wnt signalling. We show that GSK-3b enters the nucleus, forms a complex with b-catenin and lowers the levels of b-catenin/TCFdependent transcription in a mechanism that involves GSK-3b-Axin binding.

show abstract

“…Serine/threonine phosphorylation of nuclear translocated STAT5 dimers may support its binding of DNA or facilitate its dephosphorylation and export [36,38]. STAT5 interactions with CRM-1, the nuclear export protein that binds the NES sequence embedded in STAT5's DNA binding motif, allows for normal recycling and translocation of STAT5 proteins [36].…”

Section: Dysregulation Of Stat5-dna Interactionsmentioning

confidence: 99%

Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

Litherland

Xie

Grebe

et al. 2005

Journal of Autoimmunity

View full text Add to dashboard Cite

Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GM-CSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type 1 diabetic (T1D), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (80-77 kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94 kDa) and B (94-92 kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages.

show abstract

Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STAT protein

Cited by 67 publications

References 42 publications

Nuclear Export of NF90 to Stabilize IL-2 mRNA Is Mediated by AKT-Dependent Phosphorylation at Ser647 in Response to CD28 Costimulation

Nuclear Export of NF90 to Stabilize IL-2 mRNA Is Mediated by AKT-Dependent Phosphorylation at Ser647 in Response to CD28 Costimulation

Nuclear GSK-3β inhibits the canonical Wnt signalling pathway in a β-catenin phosphorylation-independent manner

Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

Contact Info

Product

Resources

About