RARRES3 regulates signal transduction through post-translational protein modifications

Hsu, Tzu-Hui; Chang, Tsu‐Chung

doi:10.1080/23723556.2014.999512

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…As the other metalloproteinases identified in the static consensus graphs ( MMP1 and MMP10 ) are not members of cluster 2, but of the immediately positively regulated cluster 1, it can be assumed, that TIMP1 activation might also have a negative regulatory impact on these late after EGF stimulation. In the delayed downregulated cluster 3 we observe RARRES3, the retinoic acid receptor responder 3, which is known for its growth inhibitory effects (Hsu and Chang, 2015 ). A late downregulation thus can have the function of preventing contrasting growth signals.…”

Section: Discussionmentioning

confidence: 96%

Decoding Cellular Dynamics in Epidermal Growth Factor Signaling Using a New Pathway-Based Integration Approach for Proteomics and Transcriptomics Data

Wachter

Beißbarth

2016

Front. Genet.

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Identification of dynamic signaling mechanisms on different cellular layers is now facilitated as the increased usage of various high-throughput techniques goes along with decreasing costs for individual experiments. A lot of these signaling mechanisms are known to be coordinated by their dynamics, turning time-course data sets into valuable information sources for inference of regulatory mechanisms. However, the combined analysis of parallel time-course measurements from different high-throughput platforms still constitutes a major challenge requiring sophisticated bioinformatic tools in order to ease biological interpretation. We developed a new pathway-based integration approach for the analysis of coupled omics time-series data, which we implemented in the R package pwOmics. Unlike many other approaches, our approach acknowledges the role of the different cellular layers of measurement and infers consensus profiles and time profile clusters for further biological interpretation. We investigated a time-course data set on epidermal growth factor stimulation of human mammary epithelial cells generated on the two layers of RNA and proteins. The data was analyzed using our new approach with a focus on feedback signaling and pathway crosstalk. We could confirm known regulatory patterns relevant in the physiological cellular response to epidermal growth factor stimulation as well as identify interesting new interactions in this signaling context, such as the regulatory influence of the connective tissue growth factor on transferrin receptor or the influence of growth arrest and DNA-damage-inducible alpha on the connective tissue growth factor. Thus, we show that integrated cross-platform analysis provides a deeper understanding of regulatory signaling mechanisms. Combined with time-course information it enables the characterization of dynamic signaling processes and leads to the identification of important regulatory interactions which might be dysregulated in disease with adverse effects.

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Section: Discussionmentioning

confidence: 96%

Decoding Cellular Dynamics in Epidermal Growth Factor Signaling Using a New Pathway-Based Integration Approach for Proteomics and Transcriptomics Data

Wachter

Beißbarth

2016

Front. Genet.

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“…Subsequently, RARRES3, a hub gene of the TiME-score, attracted our additional attention as a retinol-induced class II tumor suppressor gene whose downregulation often leads to metastasis of cancer cells ( 42 ). In breast cancer, RARRES3 downregulation can lead to tumor cell adhesion involved in metastasis initiation, loss of RARRES3 phospholipase A1/A2 activity can lead to impaired tumor cell differentiation, and RARRES3 has the potential to act as an endogenous inhibitor of immunoproteasome expression ( 43 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of a RARRES3-based prognostic signature related to the specific immune microenvironment of pancreatic cancer

Sun,

Wang,

Yao

et al. 2024

Front. Oncol.

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BackgroundTumor immune microenvironment (TiME) is prognostically instructive in Pancreatic adenocarcinoma (PAAD). However, the potential value of TiME-related genes in the individualized immunotherapy of PAAD has not been clarified.MethodsCorrelation between Immune-Related Genes (IRGs) and immune-related transcription factors (TFs) was performed to prove the immune correlation of selected genes. Immune-related molecular subtypes were identified by consensus clustering. The TiME-score, an immune microenvironment-related prognostic signature for PAAD, was constructed using minimum absolute contraction and selection operator regression (Lasso-Cox). The International Cancer Genome Consortium (ICGC) dataset validated the reliability of TiME-score as external validation. Single-cell samples from GSE197177 confirmed microenvironment differences of TiME-score hub genes between tumor and its paracancer tissues. Then, RARRES3, a hub gene in TiME-score, was further analyzed about its upstream TP53 mutation and the specific immune landscape of itself in transcriptome and Single-cell level. Eventually, TiME-score were validated in different therapeutic cohorts of PAAD mice models.ResultsA 14-genes PAAD immune-related risk signature, TiME-score, was constructed based on IRGs. The differences of TiME-score hub genes in single-cell samples of PAAD cancer tissues and adjacent tissues were consistent with the transcriptome. Single-cell samples of cancer tissues showed more pronounced immune cell infiltration. The upstream mutation factor TP53 of RARRES3 was significantly enriched in immune-related biological processes. High RARRES3 expression was correlated with a worse prognosis and high macrophages M1 infiltration. Additionally, the immunohistochemistry of hub genes AGT, DEFB1, GH1, IL20RB, and TRAF3 in different treatment cohorts of mice PAAD models were consistent with the predicted results. The combination of immunotherapy, chemotherapy and targeted therapy has shown significantly better therapeutic effects than single drug therapy in PAAD.ConclusionTiME-score, as a prognostic signature related to PAAD-specific immune microenvironment constructed based on RARRES3, has predictive value for prognosis and the potential to guide individualized immunotherapy for PAAD patients.

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“…Besides being identified as a tumor suppressor, there is growing evidence suggesting that PLAAT4 also plays crucial roles in restricting tumor metastasis, the main cause of cancer-related death (Figure 3B) (13,(114)(115)(116). In this regard, PLAAT4 is among the metastasis-associated gene signatures whose expression levels in primary breast tumors inversely correlate with the frequency of lung metastasis (117).…”

Section: Mechanisms Of Plaat4 As a Tumor Suppressormentioning

confidence: 99%

“…Interestingly, while PLAAT4 dampens initial steps in the lung colonization through enforcing the retention of a phospholipase A1/2 activity-dependent differentiation features, it could also serve as an acyl protein thioesterase that hydrolyzes the acyl chains of Wnt proteins and a co-receptor in the canonical Wnt signaling to induce low density lipoprotein receptor protein 6 (LRP6). This contributes to the blockade of Wnt/b-catenin signaling, whereby suppressing epithelial-mesenchymal transition (EMT) and stem cell properties of tumor cells (114,118). It is also noteworthy that PLAAT4 is expressed at significantly lower levels in steroid hormone receptors-positive (estrogen receptor-, progesterone receptor-and estrogen/progesterone receptorspositive (ER + , PR + and ER + /PR + )) tissues than in ER-, PR-and ER/PR-negative tissues, hence providing a biomarker to identify a subgroup of patients with higher susceptibility to lung metastasis (103).…”

Section: Mechanisms Of Plaat4 As a Tumor Suppressormentioning

confidence: 99%

Phospholipase A and acyltransferase 4/retinoic acid receptor responder 3 at the intersection of tumor suppression and pathogen restriction

et al. 2023

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Phospholipase A and acyltransferase (PLAAT) 4 is a class II tumor suppressor with phospholipid metabolizing abilities. It was characterized in late 2000s, and has since been referred to as ‘tazarotene-induced gene 3’ (TIG3) or ‘retinoic acid receptor responder 3’ (RARRES3) as a key downstream effector of retinoic acid signaling. Two decades of research have revealed the complexity of its function and regulatory roles in suppressing tumorigenesis. However, more recent findings have also identified PLAAT4 as a key anti-microbial effector enzyme acting downstream of interferon regulatory factor 1 (IRF1) and interferons (IFNs), favoring protection from virus and parasite infections. Unveiling the molecular mechanisms underlying its action may thus open new therapeutic avenues for the treatment of both cancer and infectious diseases. Herein, we aim to summarize a brief history of PLAAT4 discovery, its transcriptional regulation, and the potential mechanisms in tumor prevention and anti-pathogen defense, and discuss potential future directions of PLAAT4 research toward the development of therapeutic approaches targeting this enzyme with pleiotropic functions.

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RARRES3 regulates signal transduction through post-translational protein modifications

Cited by 8 publications

References 11 publications

Decoding Cellular Dynamics in Epidermal Growth Factor Signaling Using a New Pathway-Based Integration Approach for Proteomics and Transcriptomics Data

Decoding Cellular Dynamics in Epidermal Growth Factor Signaling Using a New Pathway-Based Integration Approach for Proteomics and Transcriptomics Data

Construction and validation of a RARRES3-based prognostic signature related to the specific immune microenvironment of pancreatic cancer

Phospholipase A and acyltransferase 4/retinoic acid receptor responder 3 at the intersection of tumor suppression and pathogen restriction

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