Regulatory Roles of MAPK Phosphatases in Cancer

Low, Heng Boon; Zhang, Yongliang

doi:10.4110/in.2016.16.2.85

Cited by 159 publications

(144 citation statements)

References 126 publications

(152 reference statements)

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“…DUSP1 was the first identified family member, which is implicated in diverse biological events such as inflammation, cancer, metabolism, and diabetes [53]. DUSP1 is expressed in a variety of tissues with the highest levels being observed in the lung [37], and it is induced in the heart upon disease stimulation [54].…”

Section: Dusps In Cardiac Remodeling Through Mapk Regulationmentioning

confidence: 99%

Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs)

Liu

Molkentin

2016

Journal of Molecular and Cellular Cardiology

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Mitogen-activated protein kinases (MAPKs) play a critical role in regulating cardiac hypertrophy and remodeling in response to increased workload or pathological insults. The spatiotemporal activities and inactivation of MAPKs are tightly controlled by a family of dual-specificity MAPK phosphatases (DUSPs). Over the past 2 decades, we and others have determined the critical role for selected DUSP family members in controlling MAPK activity in the heart and the ensuing effects on ventricular growth and remodeling. More specifically, studies from mice deficient for individual Dusp genes as well as heart-specific inducible transgene-mediated overexpression have implicated select DUSPs as essential signaling effectors in the heart that function by dynamically regulating the level, subcellular and temporal activities of the extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs) and p38 MAPKs. This review summarizes recent literature on the physiological and pathological roles of MAPK-specific DUSPs in regulating MAPK signaling in the heart and the effect on cardiac growth and remodeling.

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Section: Dusps In Cardiac Remodeling Through Mapk Regulationmentioning

confidence: 99%

Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs)

Liu

Molkentin

2016

Journal of Molecular and Cellular Cardiology

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“…Phosphatase overexpression is oncogenic in different tumor types, but the signaling mechanisms remain unclear (Julien et al, 2007(Julien et al, , 2011. Recent work indicates that overexpressed phosphatases increase the malignancy of cancers that have a hyper-activated MAPK/ERK pathway (Julien et al, 2007;Low and Zhang, 2016;De Vriendt et al, 2013). Our result in the previous section suggested a mechanism through which overexpression of ERKspecific phosphatases sustains MEK phosphorylation levels ( Figures 4F and 4H).…”

Section: Pairwise Overexpression Analysis Reveals Phosphatase Sustainmentioning

confidence: 52%

“…Phosphatase overexpression is observed to drive tumor progression with unclear signaling mechanisms (Julien et al, 2011;Low and Zhang, 2016;De Vriendt et al, 2013). We indicated that rather than directly activating a cancer-driven signaling pathway, overexpression of ERKspecific phosphatases modulates signaling dynamics that leads to prolonged proliferative signal in cells.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the human kinome and phosphatome reveals diseased signaling networks induced by overexpression

Lun

Szklarczyk

Gábor

et al. 2018

Preprint

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Kinase and phosphatase overexpression drives tumorigenesis and drug resistance in many cancer types. Signaling networks reprogrammed by protein overexpression remain largely uncharacterized, hindering discovery of paths to therapeutic intervention. We previously developed a single cell proteomics approach based on mass cytometry that enables quantitative assessment of overexpression effects on the signaling network. Here we applied this approach in a human kinome-and phosphatome-wide study to assess how 649 individually overexpressed proteins modulate the cancer-related signaling network in HEK293T cells. Based on these data we expanded the functional classification of human kinases and phosphatases and detected 208 novel signaling relationships. In the signaling dynamics analysis, we showed that increased ERK-specific phosphatases sustained proliferative signaling, and using a novel combinatorial overexpression approach, we confirmed this phosphatase-driven mechanism of cancer progression. Finally, we identified 54 proteins that caused ligand-independent ERK activation with potential as biomarkers for drug resistance in cells carrying BRAF mutations.

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“…22 Recently, more and more studies show that MAPK has a critical influence on tumor chemoresistance. 23 PI3K-Akt plays a critical role in the chemoresistance of cancer cells as an important regulatory pathway for cell proliferation. 24 The abnormal activation of PI3K-Akt can lead to a massive proliferation of cancer cells and reduce the efficacy of chemotherapy drugs.…”

Section: Identification Of Chemotherapy Response Related Functionsmentioning

confidence: 99%

Screening candidate microRNA‐mRNA network for predicting the response to chemoresistance in osteosarcoma by bioinformatics analysis

Dai

Luo

et al. 2019

J of Cellular Biochemistry

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The search for biomarkers is important for providing more targeted treatments for osteosarcoma patients with chemoresistance. In this study, differentially expressed microRNAs (miRNAs) were identified from miRNA expression profiles. And the target messenger RNAs (mRNAs) of miRNA were obtained from two websites in public domains. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway by these miRNA targets suggests that they may have potential links to osteosarcoma chemoresistance. In the protein‐protein interaction (PPI) network, we screened three subnetworks and 10 hub RNAs, and analyzed through KEGG pathway and searched the PubMed database, indicating that they were significantly associated with drug resistance. Then we found 12 key mRNAs by analyzing the mRNA expression profile. Survival analyses showed that most of the 10 hub mRNAs and 12 key mRNAs had a significant influence on the prognosis of patients with chemoresistance osteosarcoma. A miRNA‐mRNA network is constructed by integrating mRNAs and miRNAs information. The network biomarkers in this study have an advantage over traditional single‐molecule biomarkers in terms of predictive power. And the mRNAs in this network biomarkers are supported by survival analysis or by existing theories. These results will contribute to the choice of chemotherapy before treatment and the prediction of patient prognosis.

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Regulatory Roles of MAPK Phosphatases in Cancer

Cited by 159 publications

References 126 publications

Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs)

Regulation of cardiac hypertrophy and remodeling through the dual-specificity MAPK phosphatases (DUSPs)

Analysis of the human kinome and phosphatome reveals diseased signaling networks induced by overexpression

Screening candidate microRNA‐mRNA network for predicting the response to chemoresistance in osteosarcoma by bioinformatics analysis

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