Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis

J Neuropathol Exp Neurol. 2006 Feb;65(2):162-75. doi: 10.1097/01.jnen.0000199575.93794.2f.


Sporadic and neurofibromatosis type 2-associated schwannomas contain a glial growth factor (GGF)-like activity that has been hypothesized to promote neoplastic Schwann cell mitogenesis. It is not known whether this GGF-like activity is neuregulin-1 (NRG-1), an epidermal growth factor (EGF)-related molecule that regulates the proliferation, survival, and differentiation of developing Schwann cells, the related factor NRG-2, or another NRG/EGF ligand. We report that neoplastic Schwann cells within schwannomas overexpress multiple alpha and beta transmembrane precursors from the class II and class III NRG-1 subfamilies. NRG-2 alpha and beta transcripts are similarly overexpressed in some tumors. Of the other 8 known NRG/EGF ligands, only heparin-binding EGF, epiregulin, and TGFalpha are detectable in schwannomas. Neoplastic Schwann cells almost uniformly express erbB2 and erbB3, 2 membrane receptor tyrosine kinases mediating NRG-1 and NRG-2 action. Expression of the NRG receptor erbB4 and EGF receptor is also evident in schwannomas, but is more limited, occurring in only a subset of these tumors. ErbB2, the preferred dimerization partner for all erbB kinases, is constitutively phosphorylated in schwannomas. These observations suggest that autocrine, paracrine, and/or juxtacrine NRG-1/NRG-2 signaling promotes schwannoma pathogenesis and that this signaling pathway may be an important therapeutic target in schwannomas.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuregulin-1
  • Neurilemmoma* / pathology
  • Neurilemmoma* / physiopathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*


  • NRG1 protein, human
  • NRG2 protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neuregulin-1
  • Protein Isoforms
  • Epidermal Growth Factor
  • Receptor, ErbB-2