O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies

Freund, Patricia; Kerényi, Marc; Hager, Martin H.; Wagner, Tobias; Wingelhofer, Bettina; Phạm, Hà; Elabd, M; Han, Xiaonan; Valent, Peter; Gouilleux, Fabrice; Sexl, Veronika; Krämer, Oliver; Groner, Bernd; Moriggl, Richard

doi:10.1038/leu.2017.4

Cited by 50 publications

(43 citation statements)

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“…By RNA sequencing of IECs, we predicted STAT proteins, particularly STAT1, as a downstream target of protein O‐GlcNAcylation and mediator of intestinal damage in Vil‐Ogt KO mice. Several STAT proteins including STAT1, STAT3, STAT5A, STAT5B, and STAT6 can be O‐GlcNAc‐modified (Gewinner et al , ; Freund et al , ). We confirmed that STAT1 in IECs was O‐GlcNAcylated, and loss of OGT reduced STAT1 expression and transcription activity.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in intestinal epithelial O‐GlcNAcylation predisposes to gut inflammation

et al. 2018

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Post‐translational modifications in intestinal epithelial cells (IECs) allow for precise control in intestinal homeostasis, the breakdown of which may precipitate the pathological damage and inflammation in inflammatory bowel disease. The O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) modification on intracellular proteins controls diverse biological processes; however, its roles in intestinal homeostasis are still largely unexplored. Here, we found that levels of protein O‐GlcNAcylation and the expression of O‐GlcNAc transferase (OGT), the enzyme adding the O‐GlcNAc moiety, were reduced in IECs in human IBD patients. Deletion of OGT specifically in IECs resulted in disrupted epithelial barrier, microbial dysbiosis, Paneth cell dysfunction, and intestinal inflammation in mice. Using fecal microbiota transplantation in mice, we demonstrated that microbial dysbiosis although was insufficient to induce spontaneous inflammation but exacerbated chemical‐induced colitis. Paneth cell‐specific deletion of OGT led to Paneth cell dysfunction, which might predispose mice to chemical‐induced colitis. On the other hand, the augmentation of O‐GlcNAc signaling by inhibiting O‐GlcNAcase, the enzyme removing O‐GlcNAcylation, alleviated chemical‐induced colitis. Our data reveal that protein O‐GlcNAcylation in IECs controls key regulatory mechanisms to maintain mucosal homeostasis.

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Section: Discussionmentioning

confidence: 99%

Deficiency in intestinal epithelial O‐GlcNAcylation predisposes to gut inflammation

et al. 2018

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“…In addition, crosstalk was hypothesized to also occur between tyrosine phosphorylation and O-GlcNAcylation [101], which sites were later validated using a peptide microarray screening study by Pieters and coworkers [102]. One specific example occurs on STAT5, where O-GlcNAcylation of STAT5 controls tyrosine phosphorylation [103]. These disjointed examples show that phosphorylation/O-GlcNAcylation crosstalk at nearby sites in proteins is a generic feature in cellular signaling.…”

Section: Phosphorylation/o-glcnacylation Crosstalk At the Substrate Lmentioning

confidence: 97%

“…Indeed, this 'proximity' type of crosstalk features in many biological systems fine-tuning activity. One specific example occurs on STAT5, where O-GlcNAcylation of STAT5 controls tyrosine phosphorylation [103]. Also in NF-jB signaling, p65 is O-GlcNAcylated at Thr305 and Ser319, where phosphorylation at Thr308 may prevent O-GlcNAcylation at Thr305 [100].…”

Section: Phosphorylation/o-glcnacylation Crosstalk At the Substrate Lmentioning

confidence: 99%

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

2018

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A wide variety of protein post-translational modifications (PTMs) decorate cellular proteins, regulating their structure, interactions and ultimately their function. The density of co-occurring PTMs on proteins can be very high, where multiple PTMs can positively or negatively influence each other's actions, termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, whereby we focus on crosstalk between protein phosphorylation and O-GlcNAcylation. These two PTMs largely target identical (i.e., Ser and Thr) amino acids in proteins. Phosphorylation/O-GlcNAcylation crosstalk comes in many flavors, for instance by competition for the same site/residue (reciprocal crosstalk), as well as by modifications influencing each other in proximity or even distal on the protein sequence. PTM crosstalk is observed on the writers of these modifications (i.e., kinases and O-GlcNAc transferase), on the erasers (i.e., phosphatases and O-GlcNAcase), and on the readers and the substrates. We describe examples of all these different flavors of crosstalk, and additionally the methods that are emerging to better investigate in particular phosphorylation/O-GlcNAcylation crosstalk.

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“…Therefore, the constitutive activity of STAT5 H298R/S710F is modest and limited by the bioavailability of wild-type STAT5 to pair with. By contrast, the single STAT5 S710F mutant exerts a strong constitutive activity in both CD8 T cells [81] and Ba/F3 cells [82].…”

Section: Role Of Stat5 In the Generation Of Memory Cd8 T Cells And Mamentioning

confidence: 93%

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Verdeil

Lawrence

Schmitt-Verhulst

et al. 2019

Cancers

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Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients. function of tumor-associated macrophages (TAM) and (ii) for the regulation of T cell functions. As STAT TFs are key players in the regulation of functions of these immune cells, their manipulation can have a beneficial or detrimental effect on the anti-tumor response depending on the targeted cell type. Tumor-Induced Inflammation Drives Accumulation of Tumor-Infiltrating Myeloid CellsCytokine receptor-induced signaling sustains and amplifies the activation of STAT3, NF-κB and AP-1 in a positive amplification loop, fueling tumor-associated inflammation. As such, a core inflammation-related gene set regulated by STAT3, NF-κB and AP-1 has recently been proposed as an "inflammatory index" in breast cancer cell lines and patient samples [4]. Importantly, in correlation with this inflammatory index, this study reported a concerted regulation of (i) non-inflammatory genes related to angiogenesis, metastasis, and cell proliferation; (ii) tumor genome instability; and (iii) heterogeneity of the tumor microenvironment (TME), including the recruited immune cells. Remarkably, these co-regulated characteristics were found across several cancer types driven by distinct oncogenes [4].Tumor-derived cytokines have been linked to the accumulation of immune-suppressive myeloid cells including both myeloid-derived suppressor cells (MDSCs; IMCs) and tumor-associated macrophages (TAM). In both human and mouse melanomas, IMCs have an important role in malignant progression and evasion from anti-tumor immunity that is linked to the suppression of T cell responses [6][7][8][9]. While increased...

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O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies

Cited by 50 publications

References 49 publications

Deficiency in intestinal epithelial O‐GlcNAcylation predisposes to gut inflammation

Deficiency in intestinal epithelial O‐GlcNAcylation predisposes to gut inflammation

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

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