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  • Original Paper
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Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

Oncogene volume 19, pages 3999–4010 (2000)Cite this article

Abstract

Several growth factors and cytokines, including EGF, are known to induce tyrosine phosphorylation of Signal Regulatory Proteins (SIRPs). Consistent with the idea that increased phosphorylation activates SIRP function, we overexpressed human SIRPα1 in U87MG glioblastoma cells in order to examine how SIRPα1 modulates EGFR signaling pathways. Endogenous EGFR proteins are overexpressed in U87MG cells and these cells exhibit survival and motility phenotypes that are influenced by EGFR kinase activity. Overexpression of the SIRPα1 cDNA diminished EGF-induced phosphoinositide-3-OH kinase (PI3-K) activation in U87MG cells. Reduced EGF-stimulated activation of PI3-K was mediated by interactions between carboxyl terminus of SIRPα1 and the Src homology-2 (SH2)-containing phosphotyrosine phosphatase, SHP2. SIRPα1 overexpression also reduced the EGF-induced association between SHP2 and the p85 regulatory subunit of PI3-K. Inhibition of transformation and enhanced apoptosis following γ-irradiation were observed in SIRPα1-overexpressing U87MG cells, and enhanced apoptosis was associated with reduced levels of bcl-xL protein. Furthermore, SIRPα1-overexpressing U87MG cells displayed reduced cell migration and cell spreading that was mediated by association between SIRPα1 and SHP2. However, SIRPα1-overexpressing U87MG clonal derivatives exhibited no differences in cell growth or levels of mitogen-activated protein kinase (MAPK) activation. These data reveal a pathway that negatively regulates EGFR-induced PI3-K activation in glioblastoma cells and involves interactions between SHP2 and tyrosine phosphorylated SIRPα1. These results also suggest that negative regulation of PI3-K pathway activation by the SIRP family of transmembrane receptors may diminish EGFR-mediated motility and survival phenotypes that contribute to transformation of glioblastoma cells.

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Acknowledgements

This work was supported by grants from the Veterans Administration Merit Review Program and The Brain Tumor Society to DM O'Rourke. This work was also supported by grants from the National Cancer Institute, the American Cancer Society, and the Abramson Family Cancer Center to MI Greene.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Chuan-jin Wu, Mark I Greene & Donald M O'Rourke

  2. Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Donald M O'Rourke

  3. Department of Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Mark I Greene & Donald M O'Rourke

  4. Max-Planck-Institut Fur Biochemie, Am Klopferspitz 18A, Martinsried, 82152, Germany

    Zhengjun Chen & Axel Ullrich

  5. School of Life Science, University of Science and Technology of China, Hefei, 230027, Anhui, P.R. China

    Chuan-jin Wu

  6. Abramson Family Cancer Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Mark I Greene

  7. Department of Surgery (Neurosurgery), Philadelphia Veterans Administration Medical Center, University and Woodland Avenues, Philadelphia, 19104, Pennsylvania, PA, USA

    Donald M O'Rourke

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Wu, Cj., Chen, Z., Ullrich, A. et al. Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs). Oncogene 19, 3999–4010 (2000). https://doi.org/10.1038/sj.onc.1203748

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