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https://doi.org/10.1371/journal.pone.0171464
Title: | Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif) | Authors: | Ng M.Y. Wang M. Casey P.J. Gan Y.-H. Hagen T. |
Keywords: | bacterial protein BIM protein cullin cycle inhibiting factor growth factor receptor bound protein 2 mitogen activated protein kinase SOS protein unclassified drug bacterial protein mitogen activated protein kinase protein tyrosine phosphatase virulence factor apoptosis Article Burkholderia pseudomallei cell membrane controlled study deamination embryo enzyme activation enzyme inhibition human human cell nonhuman protein domain protein phosphorylation signal transduction Burkholderia pseudomallei cell line chemistry gene expression genetics melioidosis metabolism microbiology pathogenicity phosphorylation Bacterial Proteins Bcl-2-Like Protein 11 Burkholderia pseudomallei cdc25 Phosphatases Cell Line Enzyme Activation Extracellular Signal-Regulated MAP Kinases Gene Expression Humans MAP Kinase Signaling System Melioidosis Phosphorylation Protein Interaction Domains and Motifs SOS1 Protein Virulence Factors |
Issue Date: | 2017 | Publisher: | Public Library of Science | Citation: | Ng M.Y., Wang M., Casey P.J., Gan Y.-H., Hagen T. (2017). Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif). PLoS ONE 12 (2) : e0171464. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0171464 | Abstract: | Cycle inhibiting factors (Cifs) are virulence proteins secreted by the type III secretion system of some Gram-negative pathogenic bacteria including Burkholderia pseudomallei. Cif is known to function to deamidate Nedd8, leading to inhibition of Cullin E3 ubiquitin ligases (CRL) and consequently induction of cell cycle arrest. Here we show that Cif can function as a potent activator of MAPK/ERK signaling without significant activation of other signaling pathways downstream of receptor tyrosine kinases. Importantly, we found that the ability of Cif to activate ERK is dependent on its deamidase activity, but independent of Cullin E3 ligase inhibition. This suggests that apart from Nedd8, other cellular targets of Cifdependent deamidation exist. We provide evidence that the mechanism involved in Cifmediated ERK activation is dependent on recruitment of the Grb2-SOS1 complex to the plasma membrane. Further investigation revealed that Cif appears to modify the phosphorylation status of SOS1 in a region containing the CDC25-H and proline-rich domains. It is known that prolonged Cullin E3 ligase inhibition leads to cellular apoptosis. Therefore, we hypothesize that ERK activation is an important mechanism to counter the pro-apoptotic effects of Cif. Indeed, we show that Cif dependent ERK activation promotes phosphorylation of the proapoptotic protein Bim, thereby potentially conferring a pro-survival signal. In summary, we identified a novel deamidation-dependent mechanism of action of the B. pseudomallei virulence factor Cif/CHBP to activate MAPK/ERK signaling. Our study demonstrates that bacterial proteins such as Cif can serve as useful molecular tools to uncover novel aspects of mammalian signaling pathways. © 2017 Ng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | Source Title: | PLoS ONE | URI: | https://scholarbank.nus.edu.sg/handle/10635/166021 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0171464 |
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