Mitogen-activated protein kinase pathways are evolutionarily conserved kinase modules that link extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, migration and apoptosis. The mammalian MAPK family consists of ERK, p38, and JNK. Each of these enzymes exists in several isoforms: ERK1 to ERK8;p38-Alpha,-Beta,-Gamma,and -Delta; and JNK1 to JNK3. Each MAPK signaling axis comprises at least three components: a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. MAP3Ks phosphorylate and activate MAP2Ks, which in turn phosphorylate and activate MAPKs (Ref.1 and 2). The ERK1/2 cascade plays pivotal roles in proliferation, differentiation, tumorigenesis and other physiological processes. ERK1/2 cascade acts downstream of Ras and usually involves sequential phosphorylation and activation of the MAP3KRaf-1, B-Raf, and A-Raf; ERK kinases (MEK)1/2; ERK1/2 ; and MAPKAPKs. The activation of the ERK1/2 cascade is mostly initiated at membrane receptors, such as RTKs, GPCRs, ion channels and others. These receptors transmit the signal by recruiting GRB2 and SOS that induces the activation of Ras and then Raf. About 200 distinct substrates of ERK1/2 have been identified to date, some of which include PLA2, Elk1, c-Fos, and c-Jun (Ref.3 and 4). ERK3 and ERK4 belong to the group of atypical MAPKs. The phosphorylation of ERK3 and ERK4 proceeds through upstream protein kinases, such as PAKs. ERK3 also interacts with CDC14A (Ref.5), MAPK-activated protein kinase 5 (MK5) and SRC-3 (Ref.6). ERK5 is expressed in a variety of tissues and is activated by a range of growth factors, cytokines and cellular stresses. The known ERK5 substrates include the MEF2 family members, MEF2A, MEF2C and MEF2D, and the ETS-like transcription factor SAP1A (Ref.7 and 8).
The second most widely studied MAPK cascade is the JNK/SAPK, which are encoded by at least three genes: SAPK-Alpha/JNK2, SAPK-Beta/JNK3, and SAPK-Gamma/JNK1. JNKs can be activated by several different stimuli including growth factors, cytokines and stress factors. Signaling pathways that initiate apoptosis include extrinsic pathways initiated by death receptors such as those of TNF-Alpha, TRAIL and FasL, and intrinsic pathways initiated by mitochondrial events. In response to specific stimuli, MKK4 or MKK7 activates JNKs by phosphorylating the Thr and Tyr residues of the TXY motif within the activation loop of the respective JNKs (Ref.9 and 10). Upon activation by the upstream MAP2Ks, the phosphorylated JNK translocates to the nucleus where it phosphorylates and transactivates c-Jun and c-Fos. JNK can also phosphorylate several other transcription factors including JunD, ATF2, ATF3, Elk-1, Elk-3, p53, RXR-Alpha, RAR-Beta, AR, NFAT4, HSF-1and c-Myc (Ref.9 and 10).
The p38 is most well-characterized member of the MAPK family. Four p38 MAPKs have been cloned so far in higher eukaryotes: p38-Alpha/XMpk2/CSBP, p38-Beta /p38-Beta22, p38-Gamma /SAPK3/ERK6, and p38-Delta /SAPK4. The mammalian p38 MAPK families are activated by cellular stress including UV irradiation, Heat shock, High osmotic stress, lipopolysaccharide, Protein synthesis inhibitors, proinflammatory cytokines such as IL-1and TNF-Alpha and certain mitogens. The upstream MAPK cascade in p38 activation includes MAPKKKs such as ASK1, MEKK1, MEKK4, MLK2 and MLK3, DLK, TPL2, TAK1 and TAO1/ TAO2, which phosphorylate and activate MKK3 and MKK6, which in turn phosphorylate and activate p38 (Ref.11). G-proteins activate p38 via PKA or PKC, whereas stress activates p38 via Rac and CDC42. Following its activation, p38 translocates to the nucleus and phosphoryates proteins like ATF2, MAPKAPK2, STAT1, Max / Myc complexes, Elk1 and CREB through the activation of MSK1. The p38 subfamily is also involved in affecting Cell Motility, Transcription and Chromatin Remodeling. Other substrates of the p38 signaling pathway include CHOP as well as MNK1. p38 MAPK is a crucial mediator in the NF-kappaB -dependent gene activation induced by TNF (Ref.12, 13 and 14). MAPK pathways are involved in many pathological conditions, including cancer and other diseases. Therefore, a better understanding of the relationship between MAPK signal transduction system and the regulation of cell proliferation is essential for the rational design of novel pharmacotherapeutic approaches (Ref.15 and 16).