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  • Epithelial mesenchymal transition EMT is the process

    2023-11-22

    Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells are trans-differentiated into motile mesenchymal cells. During EMT, epithelial cells reorganize their cortical mu agonist cytoskeleton, lose their junctions and apical-basal polarity, change cell shape, and reprogram gene expression, which result in increased motility and invasion of individual cells [31], [32]. EMT is essential in development, wound healing, and pathologically contributes to fibrosis and cancer progression [32], [33], [34]. Rho GTPases regulate actin dynamics and control actin rearrangement during EMT. Among the Rho family proteins, RhoA, Rac1, and CDC42 promote actin stress fiber, and lamellipodia and filopodia formation, respectively [35]. It has been reported that, upon regulation by RAC1 or CDC42, kinase p21 activated kinase 1 (PAK1) activates its downstream targets involved in cell spreading and motility [36]. Moreover, Rho GTPases are responsible for the formation of cell-cell junction complexes and stabilization of adherens junctions. During EMT, cytoplasmic p120 is generated, which represses Rho activity and causes the dissociation of cell junctions. In turn, this activates Rac and CDC42 to induce the formation of membrane protrusions and cell motility [37].
    Results
    Discussion and conclusions PRP4 mediates actin filament redistribution and morphological changes in cancer cells by regulating Rho family proteins with an unclear mechanism [5]. Cofilin, one of the most important downstream targets of RhoA, is actively involved in actin filament severing, nucleation, and creation of free barbed and pointed ends available for polymerization or depolymerization depending on the local actin monomer concentration [41]. Phosphorylation of Ser3, the most important phosphorylation site involved in cofilin regulation, inhibits all cofilin-actin interactions and severing of F-actin. Additionally, cofilin activity is regulated by phosphorylation of other amino acidic residues. Previous studies reported that protein kinase Cα (PKCα)-dependent phosphorylation at Ser23 and Ser24 terminates histamine degranulation, whereas phosphorylation at Tyr68 by constitutively active proto-oncogene tyrosine-protein kinase (SRC) promotes ubiquitin-mediated cofilin degradation [42], [43]. Moreover, other reports stated that RhoA regulates its major target ROCK, which directly phosphorylates LIMK, which, in turn, phosphorylates cofilin at Ser3, thus making it inactive [13], [14], [15]. Cofilin inactivation leads to F-actin stabilization, redistribution of cytoplasmic actin, and formation of actin stress fibers. In this study, PRP4 over-expression inhibited RhoA activity and, ultimately, induced cofilin dephosphorylation, which suggests that PRP4 may regulate actin filament redistribution and induce morphological changes via cofilin activation. Furthermore, MALDI-TOF analysis evidenced that PRP4 over-expression positively regulated PP1A, which was further confirmed by RT-PCR and western blotting studies. These results strongly suggest that, besides RhoA pathway inhibition, PRP4 over-expression may induce cofilin dephosphorylation via positively regulating PP1A. Moreover, our analysis confirmed that OA inhibits PRP4-induced actin filament redistribution and morphological alterations in HCT116 cells. Although it is straightforward that PRP4 induces cofilin dephosphorylation via regulating PP1A, what relationship exists between PRP4 and PP1A and how PRP4 regulates PP1A activity remain unclear. Moreover, since PP1A is not a cofilin-specific phosphatase [19], the mechanism involved in PP1A-induced cofilin dephosphorylation needs to be unveiled. As shown in Fig. 3b, OA alone does not regulate phosphorylated cofilin levels, while it significantly elevated p-Erk and p-Raf levels (Supplemental Fig. S1). Additionally, since PRP4 over-expression did not regulate CIN protein levels (Figs. 1e, 3b), the possibility of PRP4-induced cofilin dephosphorylation via CIN was excluded. Also the CIN and SSH silencing through siRNA could not affect the PRPR-mediated downregulation of p-cofilin significantly. Therefore, further investigations are needed to uncover the underlying mechanism of PRP4-induced PP1A and cofilin activation.