Mitogen-activated protein kinase mediated intracellular signal transduction

Mitogen-activated protein (MAP) kinases are important mediators involved in the intracellular network of interacting proteins that transduce extracellular cues to intracellular responses. The ERK ("extracellular signal-regulated kinase") cascade is the best studied MAP kinase signaling pathway and may be considered as the archetypal MAP kinase cascade. The utilization of powerful molecular genetic tools helped to elucidate the existence of new MAP kinase isoforms (SAPK "stress-activated protein kinase", p38 MAP kinase) in mammalian cells. These MAP kinases respond to distinct extracellular stimuli and have different intracellular substrates. A common feature of all MAP kinase isoforms is the requirement for phosphorylation of both threonine and tyrosine regulatory sites by a specific upstream protein kinase for activation. Thus, not only protein kinases that catalyze phosphorylation, but also protein phosphatases that are capable of dephosphorylation and thereby inactivation of MAP kinases are of interest in the regulation of these intracellular signaling pathways. A diverse array of extracellular signals utilize MAP kinase signaling cascades to initiate a variety of cell signaling outcomes. The pleiotropic potential of MAP kinases emphasizes the importance of a tight control of their activation. In response to extracellular stimuli MAP kinases regulate the transcriptional activity of several transcription factors via phosphorylation, thereby initiating the expression of a variety of genes. MAP kinases have not only been suggested to play a pivotal role in fundamental cellular processes like DNA synthesis, progression through the cell cycle and cellular proliferation but have also been implicated in G1 phase arrest, induction of apoptosis and cellular differentiation. Furthermore, recent data emphasize the physiological relevance of MAP kinase cascades in the renal and cardiovascular system, since the proliferation of smooth muscle cells following balloon injury, the renal cell carcinoma as well as the rapidly progressive glomerulonephritis were shown to be accompanied by activation of ERK.