Constitutive activation of the neuregulin-1/erbB signaling pathway promotes the proliferation of a human peripheral neuroepithelioma cell line.
Neuregulin-1 (NRG-1) proteins, acting through their erbB receptors, promote the differentiation, survival and/or proliferation of many cell types in the developing nervous system, including neural crest cells and neural crest-derived Schwann cells. We have recently found that the proliferation of a neoplastic Schwann cell line is dependent on constitutive activation of the NRG-1/erbB signaling pathway and that overexpression of NRG-1 in myelinating Schwann cells induces the formation of malignant peripheral nerve sheath tumors. These observations suggested that NRG-1 might similarly promote mitogenesis in a variety of neural neoplasms including peripheral neuroepitheliomas, aggressive neural crest-derived neoplasms that arise in nerves and soft tissues. To test this hypothesis, we examined the expression of NRG-1 and its erbB receptors in SK-N-MC neuroepithelioma cells. SK-N-MC cells expressed multiple NRG-1 proteins and mRNAs encoding several alpha and beta isoforms from the sensory and motor neuron-derived factor NRG-1 subfamily as well as the NRG-1 receptor subunits erbB2, erbB3, and erbB4. The erbB receptors expressed by SK-N-MC cells were constitutively tyrosine phosphorylated and inhibiting these kinases with the erbB specific inhibitor PD158780 reduced SK-N-MC DNA synthesis in a dose-dependent manner. We conclude that constitutive activation of the NRG-1/erbB signaling pathway promotes the proliferation of SK-N-MC neuroepithelioma cells in vitro and hypothesize that NRG-1/erbB autocrine, paracrine or juxtacrine signaling may contribute to the development and/or progression of neuroepitheliomas in vivo.
Fallon
Kenneth B
KB
Division of Neuropathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Havlioglu
Necat
N
Hamilton
Leo H
LH
Cheng
Tammy P H
TP
Carroll
Steven L
SL
D002455:Cell Division; D004273:DNA, Neoplasm / Q000096:biosynthesis; D066246:ErbB Receptors / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020890:Neuregulin-1; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D066247:Receptor, ErbB-4; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049312:Receptors, Lysophospholipid; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D004273:DNA, Neoplasm; D066246:ErbB Receptors; D006133:Growth Substances; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D014443:Tyrosine; C094131:NRG1 protein, human; C587689:ERBB4 protein, human