Dual-Specificity Protein Phosphatases Targeting Extracellular Signal-Regulated Kinases: Friends or Foes in the Biology of Cancer?

Dual-specificity protein phosphatases (DUSPs) are a family of proteins that dephosphorylate both phospho-serine/threonine and phospho-tyrosine residues of Mitogen-Activated Protein Kinases (MAPKs). MAPKs are involved in a large number of cellular processes, including proliferation, differentiation, apoptosis, and stress responses. Therefore, dysregulation or improper functioning of the MAPK signalling is involved in the onset and progression of several diseases, including cancer. Likewise, dysregulation of DUSPs markedly affects cancer biology. The importance of MAPKs in the modulation of tumour development has been known for a long time, and MAPKs are consistently used as molecular targets for cancer therapy. However, in the last decade, DUSPs have acquired a greater interest as possible therapeutic targets to regulate MAPK activity and to prevent resistance mechanisms to MAPK-targeting therapies. Moreover, the possibility of exploiting DUSPs as biomarkers for the diagnosis and prognosis of specific types of cancer is also emerging. In this review, we report what is known in the literature on the role of DUSPs in cancer onset and progression, focusing on those targeting the extracellular signal-regulated kinases (ERKs), in particular ERK1/2 and ERK5 conventional MAPKs. The specific role of each ERK-targeting DUSP in supporting or hampering cancer progression in the context of different types of cancer is also discussed.