Regulatory mechanisms of mitogen-activated protein kinase cascades and their failure in human diseases

Abstract

In eukaryotic cells, a wide array of extracellular stimuli generates intracellular signals that converge on a limited number of protein kinase cascades, commonly referred to as mitogen-activated protein kinase (MAPK) pathways. MAPK cascades (MAPKKK-MAPKK-MAPK) are the major signaling systems that dictate cell fate decisions such as, proliferation, differentiation, and apoptosis. There are at least three subfamilies of MAPKs, named p38, JNK, and ERK in human cells. The ERK subfamily members are activated by mitogenic stimuli and are associated with cell proliferation. In contrast, JNK and p38 are activated by environmental stresses (e.g., DNA damage or osmotic shock) and by cytokines (e.g., TNFα), and play pivotal roles in cellular stress responses. Thus, p38 and JNK are collectively called stress-activated MAPKs. Perturbation of these critical signaling systems is involved in a variety of life-threatening disorders, including cancer and auto-immune diseases. Therefore, these signaling systems are of clinical importance. We previously identified several molecules that regulate MAPK pathways, such as MTK1, GADD45, PP2C, and MCRIP1, and showed that some of these molecules were indeed aberrantly regulated in human cancer. In this review, I will discuss resent findings concerning the regulation of MAPK signaling in cell fate decision and outline some of the major findings from our laboratory.