Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer Gen Sheng Wu Published online: 24 August 2007 # Springer Science + Business Media, LLC 2007 Abstract The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are a family of dual-specificity protein phosphatases that dephosphorylate both phospho- threonine and phospho-tyrosine residues in MAP kinases, including the c-Jun N-terminal protein kinase (JNK)/stress- activated protein kinase (SAPK), the p38 MAPK, and the extracellular signal-related kinase (ERK). Since phosphor- ylation is required for the activation of MAP kinases, dephosphorylation by MKPs inhibits MAPK activity, thereby negatively regulating MAPK signaling. It is known that deregulation of MAPK signaling is the most common alteration in human cancers. Recent studies have suggested that MKPs play an important role not only in the development of cancers, but also in the response of cancer cells to chemotherapy. Thus, understanding the roles of MKPs in the development of cancer and their impact on chemotherapy can be exploited for therapeutic benefits for the treatment of human cancer. Keywords Cancer . MKP . MAPKs 1 Introduction Mitogen-activated protein kinases (MAPKs) are major signaling transduction molecules that play an important role in regulating a variety of cellular responses, including cell proliferation, differentiation, and apoptosis. Mammali- an MAPKs mainly consist of three subfamilies; the Jun N-terminal kinases (JNKs), the p38 kinases, and the extracel- lular signal-related kinases (ERKs) [1, 2]. MAPKs can be activated by diverse stimuli including growth factors and cellular/extracellular stresses. In response to stimuli, MAPKs are activated through the reversible phosphoryla- tion of both threonine and tyrosine residues of the TXY motif in the catalytic domain by upstream dual-specificity kinases. These upstream kinases, namely MKK (MAP kinase kinase), include MKK1/2, MKK3/6, and MKK4/7, which are in turn activated by MAPK kinase kinases (MKKK or MEKK) [3–5]. Once activated, MAPKs phosphorylate a number of substrates and subsequently activate many signaling pathways, which lead to diverse outcomes including cell proliferation and apoptosis [4]. Since phosphorylation is required for the activation of MAPKs, it has become clear that dephosphorylation of MAPKs by members of the MAPK phosphatase (MKP) family plays a critical role in negatively regulating MAPK signaling transduction pathways. Recent studies have suggested that MKPs are involved in the development of cancer and have an important impact on the responses of cancer cells to chemotherapy. This review focuses on the role of MKPs in cancer development and discusses the progress that has been made for developing MKP inhibitors as novel anticancer agents. 2 MAPK phosphatases The MAPK phosphatases are a family of dual-specificity protein phosphatases (DUSP) that can dephosphorylate both phospho-threonine and phospho-tyrosine residues, Cancer Metastasis Rev (2007) 26:579–585 DOI 10.1007/s10555-007-9079-6 This paper received support from NIH grant R01 CA100073 and Elsa U. Pardee Foundation. G. S. Wu (*) Program in Molecular Biology and Genetics, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA e-mail: wug@karmanos.org