Multivariate signaling regulation by SHP2 differentially controls proliferation and therapeutic response in glioma cells

J Cell Sci. 2014 Aug 15;127(Pt 16):3555-67. doi: 10.1242/jcs.150862. Epub 2014 Jun 20.


Information from multiple signaling axes is integrated in the determination of cellular phenotypes. Here, we demonstrate this aspect of cellular decision making in glioblastoma multiforme (GBM) cells by investigating the multivariate signaling regulatory functions of the protein tyrosine phosphatase SHP2 (also known as PTPN11). Specifically, we demonstrate that the ability of SHP2 to simultaneously drive ERK1/2 and antagonize STAT3 pathway activities produces qualitatively different effects on the phenotypes of proliferation and resistance to EGFR and c-MET co-inhibition. Whereas the ERK1/2 and STAT3 pathways independently promote proliferation and resistance to EGFR and c-MET co-inhibition, SHP2-driven ERK1/2 activity is dominant in driving cellular proliferation and SHP2-mediated antagonism of STAT3 phosphorylation prevails in the promotion of GBM cell death in response to EGFR and c-MET co-inhibition. Interestingly, the extent of these SHP2 signaling regulatory functions is diminished in glioblastoma cells that express sufficiently high levels of the EGFR variant III (EGFRvIII) mutant, which is commonly expressed in GBM. In cells and tumors that express EGFRvIII, SHP2 also antagonizes the phosphorylation of EGFRvIII and c-MET and drives expression of HIF-1α and HIF-2α, adding complexity to the evolving understanding of the regulatory functions of SHP2 in GBM.

Keywords: Epidermal growth factor receptor (EGFR); Extracellular signal-regulated kinase-1/2 (ERK1/2); Gefitinib; HGF receptor (c-MET); Hypoxia inducible factors; Signal transducer and activator of transcription-3 (STAT3).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • ErbB Receptors / metabolism
  • Female
  • Gefitinib
  • Glioblastoma / drug therapy
  • Glioblastoma / enzymology*
  • Glioblastoma / genetics
  • Glioblastoma / physiopathology
  • Humans
  • Indoles / administration & dosage
  • MAP Kinase Signaling System* / drug effects
  • Mice, Nude
  • Phosphorylation / drug effects
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Quinazolines / administration & dosage
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Sulfones / administration & dosage


  • 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
  • Antineoplastic Agents
  • Indoles
  • Quinazolines
  • STAT3 Transcription Factor
  • Sulfones
  • epidermal growth factor receptor VIII
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Gefitinib