Protein kinases are ubiquitous enzymes that are able to modulate the activities of other proteins by adding phosphate groups to their tyrosine, serine, or threonine amino acids (phosphorylation). MAPKs (Mitogen-Activated Protein Kinases), which are activated by many different signals, belong to a large family of serine/threonine protein kinases that are conserved in organisms as diverse as yeast and humans . MAPKs deliver extracellular signals from activated receptors to various cellular compartments, notably the nucleus, where they direct the execution of appropriate genetic programs, including activation of gene transcription, protein synthesis, cell cycle machinery, cell death, and differentiation. A unique feature of MAPKs is that they themselves can be activated by addition of phosphate groups to both their tyrosine and threonine amino acids (dual phosphorylation) after stimulation of a receptor. Mammalian MAPK pathways can be activated by a wide variety of different stimuli acting through diverse receptor families, including hormones and growth factors that act through receptor tyrosine kinases [e.g., insulin, EGF (Epidermal Growth Factor), PDGF (Platelet-Derived Growth Factor), FGF (Fibroblast Growth Factor)] or cytokine receptors (e.g., growth hormone) to vasoactive peptides acting through G-protein coupled, seven-transmembrane receptors (e.g., ANGII, endothelin), TGF-Beta (Transforming Growth Factor-Beta)-related polypeptides, acting through Ser-Thr kinase receptors, inflammatory cytokines of the TNF (Tumor Necrosis Factor) family and environmental stresses such as osmotic shock, ionizing radiation and ischemic injury. MAPKs operate in modules composed of three protein kinases that phosphorylate and activate each other sequentially: MAPKKK (MAP Kinase Kinase Kinase) activates MAPKK (MAP Kinase Kinase), which then activates MAP Kinase. Currently, at least 14 MAPKKKs, 7 MAPKKs, and 12 MAPKs have been identified in mammalian cells. These kinase modules have been duplicated with slight variations, allowing cells to instigate multiple biological responses through a set of MAP kinase-wiring networks. In mammalian cells, three MAPK families have been clearly characterized: namely classical MAPK, also known as ERK (Extracellular signal-Regulated Kinase), JNK/SAPK (C-Jun N-terminal Kinase/ Stress-Activated Protein Kinase), and p38 Kinase [2,3].
The JNK/SAPK signaling pathway is a kinase cascade composed of different levels of MAPKs. The SAPKs are encoded by at least three genes: SAPK-Alpha/JNK2, SAPK-Beta/JNK3, and SAPK-Gamma/JNK1. As with all MAPKs, each SAPK isoform contains a characteristic Thr-X-Tyr phosphoacceptor loop in subdomain VIII of the protein kinase catalytic domain. Directly upstream of JNK, at the MAPK kinase (MAP2K) level, there are two dual specificity kinases that phosphorylate and activate JNK at serine and threonine residues. These kinases are MKK4 (MAPK Kinase-4) and MKK7. These proteins are activated, in turn, by the upstream MAP3K: MEKKs (MAPK/ERK Kinase Kinases), MLK2/3 (Mixed Lineage Kinase-2/3), TAK1 (TGF-Beta-Activated Kinase-1), TPL2 (Tumor Progression Locus-2), ZPK (Zipper Protein Kinase), and ASK1 (Apoptosis Signal-regulating Kinase-1). Some other MAP3Ks have also been identified, whose functions are not known. These included MAP3K6, MLK1, and LZK (Leucine Zipper-bearing Kinase) . Recently, a group of MAP4Ks homologous to the Ste20 kinase (an upstream member of the MAPK cascade involved in the pheromone response pathway in Saccharomyces cerevisiae) were identified and characterized. These MAP4K proteins provide another level of regulation for the MAPK/JNK signaling cascade and perhaps a link to regulatory proteins that interacts with or is located at the plasma membrane. The MAP4K group includes: HPK1 (Hematopoietic Progenitor Kinase-1), GCK (Germinal Center Kinase), GLK (GCK-Like Kinase), HGK (HPK/GCK-like Kinase), kinase homologous to Ste20/Sps1, and GCKR (GCK-Related Kinase). HPK1 is a 97-kDa serine/threonine kinase belonging to the HPK1/GCK subfamily of protein kinases. HPK1 is upstream of MEKK1 and TAK1 in the JNK kinase cascade. HPK1 associates with adaptor proteins such as Crk, CrkL, GRB2 (Growth Factor Receptor-Bound Protein-2), and Nck through binding to the SH3 (Src-Homology Domain-3) of these proteins. Furthermore, association of HPK1 with these proteins increases HPK1's kinase activity and its association with the EGF receptor. Other MAP4Ks like GCK, GCKR, GLK, GLK and HGK are all activated by TNF. Like MEKK1 and the MLKs, GCK, GCKR and HGK are specific JNK activators. JNK signal transduction pathway is implicated in multiple physiological processes. JNKs are active as dimers to translocate across the nuclear membrane. JNKs were originally identified as the major kinases responsible for the phosphorylation of c-Jun, leading to increased activity of the AP1 (Activator Protein-1) transcription factor; other nuclear transcription factors are also now known to be targets including ATF2 (Activating Transcription factor-2), Elk1, Myc, SMAD3 (Sma- and Mad-related Protein-3), tumor suppressor p53, NFAT4 (Nuclear Factor of Activator T-Cells), DPC4 (Deleted In Pancreatic Carcinoma-4) and MADD (MAP-kinase Activating Death Domain), a cell death domain protein. JNK-regulated transcription factors help to regulate gene expression in response to a variety of cellular stimuli, including stress events, growth factors, and cytokines. Activation of the JNK signaling cascade generally results in apoptosis, although it has also been shown to promote cell survival under certain conditions and has important roles in determining cell fate during metazoan development as well as involvement in tumorigenesis and inflammation [5,6].
The p38 MAPKs are a second mammalian stress-activated MAPK family. 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-1 and TNF-Alpha), and certain mitogens. At least four isoforms of p38—known as p38-Alpha, p38-Beta, p38-Gamma, and p38-Delta—have been identified, which can all be phosphorylated by the MAPK kinase MKK6. Other MAPKKs can phosphorylate some p38 isoforms. MKK3 can activate p38-Alpha, p38-Gamma, and p38-Delta. MKK4 can activate p38-Alpha. The TAK1 is a novel MAPKKK. It participates in the signal transduction of TGF-Beta and the phosphorylation of the p38 kinase pathway. The alpha and beta isoforms of p38 are responsible for the activation of HSP25/27 (Heat Shock Proteins- 25/27) and the MAPKAPK2 (MAPK-Activated Protein Kinase-2). The Gamma and Delta isoforms of p38 activate ATF2. Other transcription factors affected by the p38 family include STAT1 (Signal Transducers and Activators of Transcription-1), Max/Myc complexes, Elk-1 and CREB (cAMP Response Element-Binding Protein) through the activation of MSK1 (Mitogen- And Stress-Activated Kinase-1). Therefore, the p38 subfamily is also involved in affecting cell motility, transcription and chromatin remodeling. Other substrates of the p38 signaling pathway include CHOP (C/EBP-Homologous Protein) for regulation of gene expression, as well as MAPKAPK3, MAPKAPK5 and MNK1 (MAPK-Interacting Kinase-1). p38 MAPK is a crucial mediator in the NF-kappaB-dependent gene activation induced by TNF. p38 MAPK activation by TNF proceeds independently of the TRAF2 (TNF Receptor-Associated Factor-1)-associated NIK (NF-kappaB-Inducing Kinase), an additional MEKK, which is known to bind and activate two recently identified IKKs (I-KappaB Kinases) [7,8].
The Insulin/Mitogen-regulated ERK pathway was actually the first mammalian MAPK pathway to be identified . The ERK module responds primarily to growth factors and mitogens and stimulates transcriptional responses in the nucleus. ERK1 and ERK2, the best studied of the group, are activated by MEK1 (MAPK/ERK kinase-1) and MEK2, which phosphorylate at the Thr-Glu-Tyr motif. The MEKs, in turn, are activated by c-Raf, the MAPKKK of this signaling pathway, which is in turn regulated by growth factor receptors and tyrosine kinases activating through Ras. At the membrane, Raf is also phosphorylated by several protein kinases including Tyr kinases such as Src and Ser/Thr kinases such as PAK (p21-Activated Kinase), an effector for Rac1, a Rho family GTPase that is itself a Ras effector. Whereas Ras itself can directly influence the ERK pathway by recruiting Raf1, at least some stress-activated MAPK core pathways may be regulated by members of the Rho subfamily of the Ras superfamily. The Rho subfamily is comprised of mammals of the Rho, Rac, and CDC42 (Cell Division Cycle-42) groups. Activation of PI3K (Phosphoinositide-3-Kinase) requires Ras and, accordingly, Rho family GEFs themselves may be subject to regulation by Ras PI3K. Indeed, mitogen activation of Rac1 requires activation of PI3K. MEKK2 and MEKK3 are other MAP3Ks that can also activate MEK1 and SEK1 (SAPK/ERK Kinase-1). TPL2 can also activate the mitogenic ERK. TPL2 is a MAP3K that could directly activate MEK1 and SEK1. While overexpression of full-length TPL2 activates both the SAPKs and ERKs, expression of the oncogenic COOH-terminally truncated TPL2 results in substantially greater SAPK and ERK activation, further supporting the contention that the COOH-terminal domain negatively regulates TPL2 activity. Upon translocation to the nucleus, ERKs are responsible for the phosphorylation of multiple substrates, depending on the initial stimulus. These include activators of transcription including p90 RSK S6 kinase, MAPKAPK1 (MAPK-Activated Protein Kinase-1), Phospholipase-A2 and MSK, as well as transcription factors (Elk1, Ets1, Sap1a, m-Myc), STAT proteins such as STAT3, adapter proteins such as SOS (Son Of Sevenless), growth factor receptors such as EGF, and the estrogen receptors. Generally, activation of an ERK signaling pathway has a role in mediating cell division, migration and survival. ERK1/2 and MEK1/2 are also strongly activated during muscle exercise and may provide the link between exercise and adaptive changes in skeletal muscle composition (Ref.10). Besides the MAPK pathways recited above, other MAPK families have been identified. One of them is BMK1 (Big Mitogen-activated protein Kinase, also known as ERK5), a recently identified member of the mammalian MAPK family. BMK1 is activated by growth factors, oxidative stress, and hyperosmolar conditions. MEK5, which is activated by MEKK3, is a specific upstream kinase of BMK1. Two more ERKs (ERK3 and ERK3-Related) have also been identified, whose functions are unknown. The MAP Kinase signal transduction pathways play an important role in regulation of proliferation in mammalian cells by sharing substrate and cross-cascade interaction. MAP Kinase pathways are involved in many pathological conditions, including cancer and other diseases. Therefore, a better understanding of the relationship between MAP kinase signal transduction system and the regulation of cell proliferation is essential for the rational design of novel pharmacotherapeutic approaches [8,10].
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