MAPK阻害剤
The mitogen-activated protein (MAP) kinases are a group of evolutionarily conserved 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. They regulate several physiological and pathological cellular phenomena, including inflammation, apoptotic cell death, oncogenic transformation, tumor cell invasion, and metastasis. MAP kinases, in combination with several other signaling pathways, can differentially alter the phosphorylation status of transcription factors in a pattern unique to a given external signal. Although MAP kinases are expressed in all cell types, they regulate very specific biological responses that differ from cell type to cell type.Four major types of MAP kinase cascades have been reported in mammalian cells that respond synergistically to different upstream signals. MAP kinases are part of a threetiered phospho-relay cascade consisting of MAP kinase, a MAP kinase kinase (MEK) and a MAP kinase kinase kinase (MEKK). Controlled regulation of these cascades is involved in cell proliferation and differentiation, whereas unregulated activation of these MAP kinases can result in oncogenesis.
The most widely studied cascade is that of ERK1/ERK2 MAP kinases. In the cell, at any given time one highly active form of ERK1 or ERK2 (dual phosphorylated) exists, which exhibits over 1000-fold greater activity than the unphosphorylated form. ERKs can translocate to the nucleus to phosphorylate Elk-1 (on Ser383 and Ser389). At any one time, there may be three low activity forms of ERKs: one unphosphorylated enzyme, and two singly phosphorylated forms that contain phosphate either at a tyrosine or a threonine residue.
The JNK/SAPK cascade is activated following exposure to UV radiation, heat shock, or inflammatory cytokines. The activation of these MAP kinases is mediated by Rac and cdc42, two small G-proteins. Activated cdc42 binds to PAK protein kinase and activates it. Activated PAK65 can activate MEKK, which in turn phosphorylates SEK/ JNKK and activates it. The active SEK/JNKK phosphorylates JNK/SAPK (at the TPY motif). The sites of activating phosphorylation are conserved between ERK and JNK, however, these sites are located within distinct dual specificity phosphorylation motifs (TPY for JNK and TEY for ERK).
The p38 kinase, another member of the MAP kinase family, bears similarity to the yeast MAPK, Hog-1. It is activated in response to inflammatory cytokines, endotoxins, and osmotic stress. It shares about 50% homology with the ERKs. The upstream steps in its activation of this cascade are not well defined. However, downstream activation of p38 occurs following its phosphorylation (at the TGY motif) by MKK3, a dual specificity kinase. Following its activation, p38 translocates to the nucleus and phosphoryates ATF-2. Another known target of p38 is MAPKAPK2 that is involved in the phosphorylation and activation of heat-shock proteins.
The fourth and least studied mammalian MAP kinase pathway is big MAP kinase 1 (BMK1), also known as extracellular signal regulated kinase 5 (ERK5). BMK1 is activated in response to growth factors and stress. Activation of the BMK1 signaling pathway has not only been implicated in normal cell survival, cell proliferation, cell differentiation, but also in pathological states such as carcinogenesis, cardiac hypertrophy, and atherosclerosis. BMK1 can be activated following exposure EGF, BDNF, NGF, VEGF, FGF-2, phorbol esters, and oxidative stress. The signaling molecules in the ERK5 cascade include MEKK2/3, MEK5, and ERK5. Since BMK1 is the only known substrate of MEK5, all effects of MEK5 have been attributed to its ability to activate BMK1. Thus far, myocyte enhancer factor 2 (MEF-2), Ets-domain transcription factor (Sap1a), Bad, and serum- and glucocorticoid-inducible kinase (SGK) have been identified as substrates for BMK1.
Although different MAP kinase cascades show a high degree of specificity and functional separation, some degree of cross-talk is observed between different pathways. Another important observation is that when mammalian cells are treated with mitogenic agents, ERKs are significantly activated whereas JNK/SAPK are not affected. Conversely, cells exposed to stress activate the JNK/SAPK pathway without altering the activity of ERKs. At the transcription level, even though ATF-2 is phosphorylated and activated by all three MAP kinases, and c-Jun and Elk-1 are phosphorylated by ERKs and JNK/SAPK, all these pathways result in transcriptional activity that is unique for a particular external stress.
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Highlighted below are inhibitors included in InhibitorSelect MAPK Signaling Pathway Inhibitor Panel (Cat. No. 444189)
