SIRPalpha1 receptors interfere with the EGFRvIII signalosome to inhibit glioblastoma cell transformation and migration.
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 alpha1 (SIRPalpha1) receptors interact with SHP-2 to inhibit wild-type (wt) EGFR-mediated tumor migration, survival and cell transformation. However, the effects of SIRPalpha1 inhibitory receptors on EGFRvIII-mediated phenotypes are unclear. The aim of this study was to investigate the effect of SIRPalpha1 receptor on the EGFRvIII signalosome and phenotypes. Overexpression of SIRPalpha1 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/SIRPalpha1 cells when compared with empty vector control cells. Interestingly, SIRPalpha1 overexpression differentially modulated SHP-2 phosphorylation at tyrosyl 542 and 580 residues, which may regulate Erk1/2 activity and the EGFRvIII phenotype. In addition, SIRPalpha1-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 SIRPalpha1 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 SIRPalpha1 inhibitory receptor and the EGFRvIII signalosome may facilitate the identification of novel targets to inhibit the EGFRvIII glioblastoma phenotype.
Kapoor
G S
GS
Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
O'Rourke
D M
DM
D000943:Antigens, Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000502:physiology; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D020837:SOS1 Protein / Q000502:physiology
D000943:Antigens, Differentiation; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D020837:SOS1 Protein; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D051416:Focal Adhesion Protein-Tyrosine Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11