The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation

The MAPK cascades are central signaling pathways that regulate a wide variety of stimulated cellular processes, including proliferation, differentiation, apoptosis and stress response. Therefore, dysregulation, or improper functioning of these cascades, is involved in the induction and progression of diseases such as cancer, diabetes, autoimmune diseases, and developmental abnormalities. Many of these physiological, and pathological functions are mediated by MAPK-dependent transcription of various regulatory genes. In order to induce transcription and the consequent functions, the signals transmitted via the cascades need to enter the nucleus, where they may modulate the activity of transcription factors and chromatin remodeling enzymes. In this review, we briefly cover the composition of the MAPK cascades, as well as their physiological and pathological functions. We describe, in more detail, many of the important nuclear activities of the MAPK cascades, and we elaborate on the mechanisms of ERK1/2 translocation into the nucleus, including the identification of their nuclear translocation sequence (NTS) binding to the shuttling protein importin7. Overall, the nuclear translocation of signaling components may emerge as an important regulatory layer in the induction of cellular processes, and therefore, may serve as targets for therapeutic intervention in signaling-related diseases such as cancer and diabetes. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.