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  • br Aurora kinases br Wnt

    2024-03-04


    Aurora kinases
    Wnt signaling pathway The signal transduction pathway of Wnt/β-catenin signaling pathway plays an important role in embryogenesis to control cell differentiation and tumorigenesis [39]. A recent report indicates that 90% of colorectal cancer occur due to the activation of the Wnt signaling pathway and also in many other cancers such as prostate, breast and melanoma [40], [41], [42]. In the presence of Wnt ligand, the signal has been transmitted through frizzled receptor and it is low density lipoprotein co-receptor related protein 5/6 (LRP 5/6). These signals transmitted through dishevelled (dsh) protein that helps to activate the Wnt signaling pathway by stabilizing cytoplasmic β-catenin. Then the stabilized β-catenin further translocationd into the nucleus, where it binds to the transcription factors such as TCF/LEF (T-cell factor/lymphoid enhancing factor) to activate Wnt target genes [43], [44]. While the absence of Wnt ligand, the β-catenin has phosphorylated by the destruction complex consists of Adenomatous polyposis coli (APC), Glycogen synthase kinase 3 beta (GSK3β), Casine kinase 1 alpha (CK1α) and Axin. Then the phosphorylated β-catenin has been degraded at cytoplasm mediated through 26s ubiquitin depended proteolysis pathway [45].
    Interaction of Aurora A&B kinases and Wnt signaling pathway In mammalian cells, the inhibition of microtubule destabilizing activity of mitotic centromere associated kinesin (MCAK) either indirectly or directly regulated by Aurora A kinase. The interaction between MCAK and APC has been maintained by MT-depolymerizing kinesin, leads to merotelic attachment and lagging chromosomes [46]. Therefore, the inhibition of MCAK by Aurora A kinase is a potential way to inhibit the complex formation between APC-MCAK which leads to microtubule defect (Fig. 2). The Aurora A kinase regulates GSK3β in breast, colorectal, pancreatic, ovarian, esophageal, Caspase-8, human recombinant protein and gastric cancers [47] by phosphorylates Akt that is essential for GSK3β phosphorylation. Thus, the phosphorylated GSK3β inhibit the phosphorylation of β-catenin, which further translocation into the nucleus and activate the target genes such as c-Myc, cyclin B1 and survivin, causes proliferation and tumorigenesis (Fig. 3) [48].Thereby, the overexpression of Aurora A kinase can regulate the β-catenin level through phosphorylating GSK3β [49], [50]. It can override the checkpoint forms chromosomal instability and accumulate cells in G2/M phase that delay the mitotic entry [51] and it also interacts with axin, a novel binding partner of Aurora A kinase that affects the assembly of β-catenin destruction complex [52]. In the presence of Wnt ligand, it inhibits the destruction complex and further degrades the β-catenin, leading to increased nuclear accumulation of β-catenin [53]. This further promotes the overexpression of a G2/M target genes like Aurora A and B kinases (Fig. 4). The tumor suppressor protein APC stabilizes the microtubules during mitosis and destabilizes during interphase [54]. Especially, the EB1 (End Binding protein 1) is an important protein to regulate microtubule dynamics and microtubule based cellular process [55]. Moreover, it physically associates with the C-terminus of APC, which increases the stabilization of microtubule-kinetochore [56], [57]. It also has shown to interact with mitotic centromere-associated kinesin, which leads to increased misalignment and missegregation of chromosome, resulting in improper microtubule of kinetochore attachment [58]. EB1 also interacts with the Aurora B kinase, which has a major role in kinetochore-microtubule attachment. The phosphorylating threonine 232 residues can induce the overexpression of EB1 to inhibit the APC and upregulation of Aurora B kinase activity. Flowingly, this enhanced activity of Aurora B kinase can regulate the phosphorylation of kinetochore and chromatin substrates, which are leading to cancer development (Fig. 5) [59]. However, the phosphorylation of APC/XMCAK complex by Aurora B kinase modulates their enhanced activity [60].