Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis.
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.
Stonecypher
Mark S
MS
Department of Cell Biology, The University of Alabama at Birmingham, 1720 Seventh Avenue South, Birmingham, AL 35294, USA.
Chaudhury
Abhik Ray
AR
Byer
Stephanie J
SJ
Carroll
Steven L
SL
D000328:Adult; D000368:Aged; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1; D009442:Neurilemmoma / Q000473:pathology / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D004815:Epidermal Growth Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; C094131:NRG1 protein, human; C106766:NRG2 protein, human