Dual-Specificity MAP Kinase Phosphatases as Targets of Cancer Treatment

Abstract

The protein tyrosine phosphatase family (PTP) contains a group of dual-specificity phosphatases (DUSPs) that regulate the activivity of MAP kinases (MAPKs), which are key effectors in the control of cell growth and survival in physiological and pathological processes, including cancer. These phosphatases, named as MKP-DUSPs, include the MAPK phosphatases (MKPs) as well as a group of small-size atypical DUSPs structurally and functionally related to the MKPs. MKP-DUSPs, in most of the cases, are direct inactivators of MAPKs by dephosphorylation of both the Thr and the Tyr regulatory residues at the MAPKs catalytic loop. In some other cases, MKP-DUSPs regulate the activity of MAPKs indirectly, acting through upstream MAPK pathways components. The active involvement of MKP-DUSPs in oncogenesis or resistance to cancer therapies is now well documented, making the search and validation of MKP-DUSPs inhibitors a prominent area in clinical cancer research. Here, we review the current knowledge on the role of MKP-DUSPs in human cancer, the status of the preclinical development and validation of specific MKP-DUSP inhibitors, and the potential of MKP-DUSPs as targets for anti-cancer drugs.

Ursolic Acid Induces Apoptosis Through Mitochondrial Intrinsic Pathway and Suppression of ERK1/2 MAPK in HeLa Cells

“…DUSPs can specifically dephosphorylate one or more MAPKs (39), and substrate specificity may be dependent upon cell type and context (40 -42). DUSP 1, 2, 4, and 5 are mitogen-and stressinducible nuclear DUSPs; DUSP 6, 7, and 9 are cytoplasmic ERK-specific DUSPs; DUSP 8, 10, and 16 are JNK/p38-specific phosphatases found in both the cell nucleus and cytoplasm (43). Here, we revealed that DUSP 1, 2, 4, 5, 6, 7, and 9 mRNA expressions were up-regulated; and DUSP 14 and 16 expressions were not changed with UA treatment.…”

“…To the best of our knowledge, no one has reported that UA has potential to regulate the expression of DUSP genes in cervical carcinoma. It has been documented that DUSP 1, 2, 3, 4, 5, and 6 have emerged as potential regulators of cell growth, apoptosis, and transformation in different cell systems and human malignancies (43). Therefore, further investigations to explore the regulatory mechanisms of UA on specific DUSP gene expression in cervical cancer cells may prove to be worthwhile.…”

A Genome-Wide siRNA Screen Identifies Novel Phospho-enzymes Affecting Wnt/β-Catenin Signaling in Mouse Embryonic Stem Cells

“…Significant clusters include several members of the dual specificity phosphatase (DUSP) family (Node 250x) demonstrating up-regulation of Wnt/β-catenin dependent signaling. The DUSP family proves to be interesting due to their involvement in regulating MAPK family members which are key effectors in controlling cell growth, ES cell pluripotency and differentiation [33][34][35]. The Wnt/β-catenin signaling cascade is recently documented to be regulated by the MAPK family and activity [36].…”

Mitogen-Activated Protein Kinases and Mitogen-Activated Protein Kinase Phosphatases in Regenerative Myogenesis and Muscular Dystrophy

“…Despite the fact that the MKPs dephosphorylate a common pool of MAPKs these enzymes exhibit remarkably unique physiological effects (Chi et al, 2006;Christie et al, 2005;Wu et al, 2006). Studies from MKP knock-out mice provide convincing genetic evidence to support the notion that these MKPs function in distinct ways (Nunes-Xavier et al, 2011). The complexity of the signaling pathways and biological responses that the MKPs are involved with strongly suggest that these enzymes serve as central players in the regulation of the MAPKs.…”