Intracellular signaling cascades are the main routes of communication between the Plasma membrane and regulatory targets in various intracellular compartments. Sequential activation of Kinases is a common mechanism of signal transduction in many cellular processes. During the past decade, several related intracellular signaling cascades have been elucidated, which are collectively known as MAPK (Mitogen-Activated Protein Kinase) signaling cascades. The MAPKs are a group of protein Serine/threonine Kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. In combination with several other signaling pathways, they can differentially alter phosphorylation status of numerous proteins. There are four major groups of MAPKs in mammalian cells-the ERKs, the p38MAPKs, the JNKs and the ERK5 or BMK cascades. These MAPKs are actived by dual phosphorylation at the tripeptide motif Thr-Xaa-Tyr. Each MAPK pathway contains a three-tiered kinase cascade comprising a MAPKKK, a MAPKK and the MAPK. Frequently, a MAPKKKK activates the MAPKKK.The MAPKKK then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.p38MAPKs are members of the MAPK family that are activated by a variety of environmental stresses and inflammatory cytokines. Stress signals are delivered to this cascade by members of small GTPases of the Rho family (Rac, Rho, Cdc42). As with other MAPK cascades, the membrane-proximal component is a MAPKKK, typically a MEKK or a mixed lineage kinase (MLK). The MAPKKK phosphorylates and activates MKK3/6, the p38 MAPK kinase. MKK3/6 can also be activated directly by ASK1, which is stimulated by apoptotic stimuli. p38 MAPK is involved in regulation of Hsp27 and MAPKAP-2 and several transcription factors including ATF2, STAT1, the Max/Myc complex, MEF-2, ELK-1 and indirectly CREB via activation of MSK1.
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