Combination of targeting brokers against different signaling pathways may provide additional benefits and warrant further clinical studies [114,115]. Competing interests The authors have no relevant competing interest. Authors contributions All authors have contributed to data preparation, drafting and revising the manuscripts. kinases that play crucial roles in regulation of diverse cellular activities, including cell proliferation, survival, differentiation, motility, and angiogenesis. The MAPK pathways transduce signals from various extracellular stimuli (growth factors, hormones, cytokines and environmental stresses), leading to distinct intracellular Exatecan Mesylate responses via a series of phosphorylation events and protein-protein interactions . Four distinct MAPK cascades have been identified and named according to their MAPK module. These Tal1 are extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38 and ERK5. Each of these cascades comprised of three sequentially acting kinases, activating one after the other (MAPKKK/MAP3K, MAPKK/MAP2K, and MAPK). These signaling cascades are often dysregulated in human malignancy cells. Many small molecule inhibitors targeting various component of these cascades are moving quickly from bench to bedside [2-4]. For instance, vemurafenib is the first B-RAF inhibitor that received FDA approval in 2011 for the treatment of BRAF V600E/K mutation positive metastatic melanoma [5,6]. This review focuses on MAP2K or MAPKK component of each of the four MAPK cascades with their characteristics and the small molecule inhibitors targeting these proteins/enzymes. Mitogen-activated protein kinase or MAP2K or MAPKK are commonly known as MEK proteins. MEK proteins MEK proteins belong to a family of enzymes that lie upstream to their specific MAPK targets in each of the four MAP kinase signaling pathways and so far 7 MEK enzymes have been identified (Physique?1). These MEK enzymes selectively phosphorylate serine/threonine and tyrosine residues within the activation loop of their specific MAP kinase substrates . Open in Exatecan Mesylate a separate window Physique 1 MEK proteins and their signaling pathways. In human, four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. The corresponding MEK enyzmes and their associated signaling pathways are shown in the diagram. The molecular weight of MEK proteins ranges between 43 and 50?kDa. Like all protein kinases, they display a similar structural organization consisting of an amino-terminal domain name, a catalytic domain name which is also called the kinase domain name, and the carboxyl-terminal domain name (Physique?2). MEKs share extensive homology in their kinase domain name while the amino- and carboxy-termini are more diverse. Open in a separate window Physique 2 The structures of 7 MEK proteins. All 7 MEK proteins display a similar structural organization consisting of an amino-terminal Exatecan Mesylate domain name, a kinase domain name, and the carboxyl-terminal domain name. MEKs share extensive homology in their kinase domain name while the amino- and carboxy-termini are more diverse. MEK1 and MEK2 are closely related (Physique?2). They participate in the Ras/Raf/MEK/ERK signal transduction cascade. MEK 1, also designated as MAPKK-1, is the prototype member of MEK family proteins. It is Exatecan Mesylate encoded by the gene located on chromosome 15q22.31. The gene, genes, respectively. The genes are both located on Exatecan Mesylate chromosome 17q. MEK3 and MEK6 consist of 347 and 334 amino acids residues respectively . Structurally MEK6 differs from MEK3 in terms of C- and N- terminal regions. However, the ATP binding sites, and serine/threonine and tyrosine catalytic sites are conserved [22,23]. MEK3/6 signaling pathway is usually activated by growth factor stimulation through RTKs. Additionally, the cascade can also be activated by G-protein coupled receptors, intracellular receptors, and toll-like receptors , in response to numerous stimuli including physical and chemical stresses, hormones, UV irradiation, and cytokines, such as interleukin-1 and tumor necrosis factor. These stimuli activate different MAPK kinase kinases (MAPKKKs), which include TAK1, ASK1/2, DLK, MEKK4, TAO1/2/3 and MLK2/3 . Active MAPKKKs phosphorylate and activate MEK3/6, which in turn catalyzes the concomitant phosphorylation of a threonine/serine and a tyrosine residue in the p38 MAPK. MEK6 activates all the four isoforms of p38 MAP kinase (, , and ) whereas MEK3 can only activate p38 and p38 isoforms . p38 MAP kinase inhibits G1/S and G2/M cell cycle progression through down-regulation of cyclin D1 and Cdc25 expression respectively, both at the level of gene transcription and post-translation [26-28]. In addition, MEK3/6-p38 MAPK cascade promotes p53-dependent growth arrest by phosphorylating p53 at serine 33 and 46 . Together, these targets of MEK3/6-p38 MAPK pathway (cyclin D1, Cdc25, and p53) cooperate to arrest the cell cycle. Thus decreased p38 activity may play an important role in carcinogenesis. For example, p38 activity has been shown to be reduced in hepatocellular carcinoma in comparison to.