¹Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA

Correspondence: Dr BD Cuevas and Dr GL Johnson, Department of Pharmacology, 1108 Mary Ellen Jones Bldg., Campus Box 7365, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA. E-mails: bruce_cuevas@med.unc.edu and glj@med.unc.edu

Abstract

Mitogen-activated protein kinases (MAPKs) are members of a dynamic protein kinase network through which diverse stimuli regulate the spatio-temporal activities of complex biological systems. MAPKs regulate critical cellular functions required for homeostasis such as the expression of cytokines and proteases, cell cycle progression, cell adherence, motility and metabolism. MAPKs therefore influence cell proliferation, differentiation, survival, apoptosis and development. In vertebrates, five MAPK families are regulated by MAPK kinase kinase-MAPK kinase-MAPK (MKKK-MKK-MAPK) phosphorelay systems. There are at least 20 MKKKs that selectively phosphorylate and activate different combinations of the seven MKKs, resulting in a specific activation profile of members within the five MAPK families. MKKKs are differentially activated by upstream stimuli including cytokines, antigens, toxins and stress insults providing a mechanism to integrate the activation of different MAPKs with the cellular response to each stimulus. Thus, MKKKs can be considered as 'signaling hubs' that regulate the specificity of MAPK activation. In this review, we describe how the MKKK 'hub' function regulates the specificity of MAPK activation, highlighting MKKKs as targets for therapeutic intervention in cancer and other diseases.