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 MAPK Signaling

The MAPK (mitogen-activated protein kinase) super-family is composed of three major sets of kinases: the extracellular-receptor kinases (ERKs) and two types of MAPK-related kinases that respond to cellular stress and inflammatory signals: the c-Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) and the p38 MAPKinases. Activation of specific MAPkinases involves highly regulated and modulated cascades of phosphorylation events mediated by sequential and concerted activation of upstream kinases. ERKs are phosphorylated by members of the MEK family; JNK/SAPKs and p38 MAPKs are phosphorylated by SEKs and MKKs. These are MAPK-kinases (MAP2Ks). The MAP2Ks are phosphorylated by MAPK-kinase kinases (MAP3Ks). MAP3Kinase are the initiators of cell signals into specific MAPK cascades.

A wide variety of kinases provide MAP3K function to the MAPK pathways. MAP3Ks are activated by a wide range of signals initiated through cell receptors. TAK1, MLK, PAK, ASK1 and BRaf are MAP3Ks. Signals are typically transduced through small GTPases of the p21Ras superfamily composed of Ras, Rho and Rab families and specific kinase activities. The EGF-receptor and NGF-receptors signal the p38 and ERK MAPKs through activation of Ras-GTPase. ASK1 (apoptosis signal-regulating kinase) is an oxidative stress sensor activated by ROS-mediated dissociation of thioredoxin, binding to TNF receptor (TNFR) associated factor 2 (TRAF2) and oligomerization. ASK1 activates both p38 and JNK MAPkinases. TGF-beta activated kinase 1(TAK1) mediates signaling from the TGFbeta superfamily to p38 and ERK MAPkinases. G-protein coupled receptors also signal to MAPKs through various guanine nucleotide exchange factors (GEFs). Many GEFs are known to activate the Rho-GTPases, Rac and CDC42. Cellular and context specificity is achieved via a wide variety of guanine nucleotide exchange factors (GEFs) that activate specific GTPases in response to closely linked receptor signal inputs.