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Published on: April 29, 2022
A Crosstalk Between Dual-Specific Phosphatases and Dual-Specific Protein Kinases Can Be A Potential Therapeutic
1Hacettepe University, Faculty of Medicine, Department of Medical Biochemistry, Ankara, Turkey. basakceltics@gmail.com.
Abstract:
While protein tyrosine kinases (PTKs) play an initiative role in growth factor-mediated cellular processes, protein tyrosine phosphatases (PTPs) negatively regulates these processes, acting as tumor suppressors. Besides selective tyrosine dephosphorylation of PTKs via PTPs may affect oncogenic pathways during carcinogenesis. The PTP family contains a group of dual-specificity phosphatases (DUSPs) that regulate the activity of Mitogen-activated protein kinases (MAPKs), which are key effectors in the control of cell growth, proliferation and survival. Abnormal MAPK signaling is critical for initiation and progression stages of carcinogenesis. Since depletion of DUSP-MAPK phosphatases (MKPs) can reduce tumorigenicity, altering MAPK signaling by DUSP-MKP inhibitors could be a novel strategy in anti-cancer therapy. Moreover, Cdc25A is, a DUSP and a key regulator of the cell cycle, promotes cell cycle progression by dephosphorylating and activating cyclin-dependent kinases (CDK). Cdc25A-CDK pathway is a novel mechanism in carcinogenesis. Besides the mammalian target of rapamycin (mTOR) kinase inhibitors or mammalian target of rapamycin complex 1 (mTORC1) inhibition in combination with the dual phosphatidylinositol 3 kinase (PI3K)/mTOR or AKT kinase inhibitors are more effective in inhibiting the phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and cap-dependent translation. Dual targeting of the Akt and mTOR signaling pathways regulates cellular growth, proliferation and survival. Like the Cdc2-like kinases (CLK), dual-specific tyrosine phosphorylation-regulated kinases (DYRKs) are essential for the regulation of cell fate. The crosstalk between dual-specific phosphatases and dual- specific protein kinases is a novel drug target for anti-cancer therapy. Therefore, the focus of this chapter involves protein kinase modules, critical biochemical checkpoints of cancer therapy and the synergistic effects of protein kinases and anti-cancer molecules.
Insights
Protein tyrosine phosphatases (PTPs) and dual-specificity phosphatases (DUSPs) regulate cell growth and are implicated in cancer. Inhibiting DUSP-MAPK phosphatases (MKPs) offers a novel anti-cancer therapy strategy by targeting MAPK signaling.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein tyrosine kinases (PTKs) promote cellular processes, while protein tyrosine phosphatases (PTPs) inhibit them, acting as tumor suppressors.
- Dual-specificity phosphatases (DUSPs), a subset of PTPs, regulate Mitogen-activated protein kinases (MAPKs), crucial for cell growth, proliferation, and survival.
- Aberrant MAPK signaling and the Cdc25A-CDK pathway are implicated in carcinogenesis, highlighting DUSPs as key players in cancer development.
Purpose of the Study:
- To explore the role of dual-specific phosphatases (DUSPs) and their crosstalk with dual-specific protein kinases as novel anti-cancer drug targets.
- To investigate the therapeutic potential of targeting MAPK signaling through DUSP-MAPK phosphatase (MKP) inhibitors.
- To examine the impact of targeting signaling pathways like Akt and mTOR on cellular growth and survival in cancer therapy.
Main Methods:
- Review of literature on protein tyrosine phosphatases (PTPs), dual-specificity phosphatases (DUSPs), and Mitogen-activated protein kinases (MAPKs) in cancer.
- Analysis of the role of Cdc25A and its interaction with cyclin-dependent kinases (CDKs) in cell cycle regulation and carcinogenesis.
- Examination of signaling pathways including mammalian target of rapamycin (mTOR) and Akt, and their inhibition strategies.
Main Results:
- Depletion of DUSP-MAPK phosphatases (MKPs) can reduce tumorigenicity, suggesting DUSP-MKP inhibitors as a potential anti-cancer strategy.
- Dual targeting of Akt and mTOR signaling pathways effectively regulates cellular growth, proliferation, and survival.
- The interplay between dual-specific phosphatases and dual-specific protein kinases represents a promising area for anti-cancer drug development.
Conclusions:
- Targeting DUSP-MAPK phosphatases (MKPs) offers a novel therapeutic avenue for cancer by modulating MAPK signaling.
- Understanding the crosstalk between dual-specific phosphatases and kinases is crucial for developing effective anti-cancer therapies.
- Synergistic effects of protein kinases and anti-cancer molecules at critical biochemical checkpoints are vital for cancer treatment strategies.
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