Open Access

Molecular dissection of human oncostatin M-mediated signal transductions through site-directed mutagenesis

  • Authors:
    • Haiyan Liu
    • Cristina Fenollar-Ferrer
    • Aiqin Cao
    • Claudio Anselmi
    • Paolo Carloni
    • Jingwen Liu
  • View Affiliations

  • Published online on: February 1, 2009     https://doi.org/10.3892/ijmm_00000113
  • Pages: 161-172
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Abstract

The binding of oncostatin M (OM) to type I and type II receptor complexes elicits various biological responses by activating MEK/ERK and JAK/STAT signaling pathways. Some OM effects are clinically desirable such as reducing hyperlipidemia through the activation of hepatic LDL receptor transcription, a downstream event of ERK activation. The OM pro-inflammatory responses via induction of acute phase protein gene expression have been associated with STAT activation. In this study, by conducting site-directed mutagenesis, bioassays and molecular modeling we have defined 4 OM residues that are differently involved in the activation of ERK or STAT signaling pathway in HepG2 cells. We show that mutation of Lys163 to alanine totally abolished OM-mediated signaling, possibly because such mutation causes the disruption of a stabilizing H-bond pattern at the OM interface with receptors. G120A mutation equally impaired activations of ERK and STAT signaling pathways also by impairing the OM/cognate protein interactions. Interestingly, mutations of Gln20 and Asn123 differentially affected OM signaling through the two pathways. Q20A and N123A retained strong activity in inducing ERK phosphorylation but they showed diminished ability in activating STAT1 and STAT3. We further showed that mutations at Gln20 and Asn123 reduced OM induction of inflammatory gene fibrinogen-β to a greater extent than that of LDL receptor gene. The mutation of Asn123 is directly related to local structural modification at site 3 of OM. Collectively these results provide a structural basis of OM-mediated signaling and suggest a potential to improve OM therapeutic properties via structural modification.

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February 2009
Volume 23 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Liu H, Fenollar-Ferrer C, Cao A, Anselmi C, Carloni P and Liu J: Molecular dissection of human oncostatin M-mediated signal transductions through site-directed mutagenesis. Int J Mol Med 23: 161-172, 2009
APA
Liu, H., Fenollar-Ferrer, C., Cao, A., Anselmi, C., Carloni, P., & Liu, J. (2009). Molecular dissection of human oncostatin M-mediated signal transductions through site-directed mutagenesis. International Journal of Molecular Medicine, 23, 161-172. https://doi.org/10.3892/ijmm_00000113
MLA
Liu, H., Fenollar-Ferrer, C., Cao, A., Anselmi, C., Carloni, P., Liu, J."Molecular dissection of human oncostatin M-mediated signal transductions through site-directed mutagenesis". International Journal of Molecular Medicine 23.2 (2009): 161-172.
Chicago
Liu, H., Fenollar-Ferrer, C., Cao, A., Anselmi, C., Carloni, P., Liu, J."Molecular dissection of human oncostatin M-mediated signal transductions through site-directed mutagenesis". International Journal of Molecular Medicine 23, no. 2 (2009): 161-172. https://doi.org/10.3892/ijmm_00000113