Regulatory Roles of MAPK Phosphatases in Cancer

Abstract

The mitogen-activated protein kinases (MAPKs) are key regulators of cell growth and survival in physiological and pathological processes. Aberrant MAPK signaling plays a critical role in the development and progression of human cancer, as well as in determining responses to cancer treatment. The MAPK phosphatases (MKPs), also known as dual-specificity phosphatases (DUSPs), are a family of proteins that function as major negative regulators of MAPK activities in mammalian cells. Studies using mice deficient in specific MKPs including MKP1/DUSP1, PAC-1/DUSP2, MKP2/DUSP4, MKP5/DUSP10 and MKP7/DUSP16 demonstrated that these molecules are important not only for both innate and adaptive immune responses, but also for metabolic homeostasis. In addition, the consequences of the gain or loss of function of the MKPs in normal and malignant tissues have highlighted the importance of these phosphatases in the pathogenesis of cancers. The involvement of the MKPs in resistance to cancer therapy has also gained prominence, making the MKPs a potential target for anti-cancer therapy. This review will summarize the current knowledge of the MKPs in cancer development, progression and treatment outcomes.

Keywords: Cancer; Chemoresistance; MAPK; MKPs.

Figure 1. MAPK signaling pathways are downstream target of cellular receptor signaling, working cooperatively to regulate cell physiology.

Figure 2. Inactivation of MAPKs by MKPs (adapted from [42]). Binding of activated MAPKs to the MKB domain induces conformational changes in the DUSP domain (DSP) of the inactive MKPs, which increase of their catalytic activity.