When extracellular growth factors, ligands or cytokines bind to cell-surface receptors, conformational changes occur in these receptors altering the intracellular signaling potential of these proteins. Some of these changes may lead to the activation of Ras. Ras is a master regulator of intracellular signaling cascades and it promotes the activation of MAPK (mitogen-activated protein kinase) cascades. MAPK cascades are triple kinase pathways that include a MKKK (MAPK kinase kinase), a MKK (MAPK kinase) and a terminal MAPK A well characterized MKKK is Raf-1, that binds directly to activated GTP-bound Ras. Raf-1 binding to Ras results in post-translational modifications of Raf-1, ultimately leading to full kinase activation. Once fully activated, Raf-1 phosphorylates and activates MKK1 or MKK2 that posphorylates ERK (ERK = extracellular signal regulated kinase). The other two major MAPK cascades (besides the Raf–MKK–ERK mentioned above), are those of the Rac-MEKK-JNK (JNK = c-Jun N-terminal kinase) and Rac-MEKK-p38 MAPK Additional Important stimuli that can activate JNK and p38 MAPK cascades are cell ‘stress’ due to the accumulation of ROS (reactive oxygen species), hyperosmolarity, genotoxicity or dysfunction of the endoplasmic reticulum. Binding of apoptosis-triggering ligands like FASLG and TNF might also activated the MAPK cascade through different MKKKs. Fully activated ERK, JNK and p38 MAPK has a variety of substrates at the plasma membrane, in the cytosol and in the nucleus that regulate important aspects of cell physiology.
