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SIRPα1 receptors interfere with the EGFRvIII signalosome to inhibit glioblastoma cell transformation and migration

Oncogene volume 29, pages 4130–4144 (2010)Cite this article

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An Editorial Expression of Concern to this article was published on 01 June 2023

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Abstract

EGFRvIII, a frequent genetic alteration of the epidermal growth factor receptor (EGFR), has been shown to increase the migratory potential of tumor cells and normal fibroblasts. Previously, we showed that signal regulatory protein α1 (SIRPα1) receptors interact with SHP-2 to inhibit wild-type (wt) EGFR-mediated tumor migration, survival and cell transformation. However, the effects of SIRPα1 inhibitory receptors on EGFRvIII-mediated phenotypes are unclear. The aim of this study was to investigate the effect of SIRPα1 receptor on the EGFRvIII signalosome and phenotypes. Overexpression of SIRPα1 in U87MG.EGFRvIII cells inhibited transformation and migration in a MAPK-dependent manner, and is independent of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. We observed reduced EGFRvIII/SHP-2/Gab1/Grb2/Sos-1 interaction and enhanced SIRP/SHP-2 association in U87MG.EGFRvIII/SIRPα1 cells when compared with empty vector control cells. Interestingly, SIRPα1 overexpression differentially modulated SHP-2 phosphorylation at tyrosyl 542 and 580 residues, which may regulate Erk1/2 activity and the EGFRvIII phenotype. In addition, SIRPα1-expressing cells exhibited reduced focal adhesion kinase (FAK) phosphorylation and its recruitment to the EGFRvIII/Grb2/Sos-1/Gab1/SHP-2 complex. Collectively, our data indicate that SIRPα1 specifically affects the SHP-2/FAK/Grb2/Sos-1/MAPK activation loop to downmodulate EGFRvIII-mediated migration and transformation. Further understanding of the molecular interactions between the SIRPα1 inhibitory receptor and the EGFRvIII signalosome may facilitate the identification of novel targets to inhibit the EGFRvIII glioblastoma phenotype.

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Acknowledgements

This work was supported by grants to DMO from the National Institutes of Health R01 CA-90586, R01 2R56CA0905896-06A1 and from the Terri Ann for a Cure and For Pete's Sake Funds to the University of Pennsylvania.

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  1. Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    G S Kapoor & D M O'Rourke

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    D M O'Rourke

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  1. G S Kapoor
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Correspondence to D M O'Rourke.

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Kapoor, G., O'Rourke, D. SIRPα1 receptors interfere with the EGFRvIII signalosome to inhibit glioblastoma cell transformation and migration. Oncogene 29, 4130–4144 (2010). https://doi.org/10.1038/onc.2010.164

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