Heregulins and the ErbB-2/3/4 receptors in gliomas

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Abstract
The activation of autocrine loops involving proto-oncogene relatedreceptor tyrosine kinases has led to the analysisof a large number of growth factor systemsin human glioma specimens and cell lines. TheErbB-2 system, also called HER-2 or neu, isanalogous to the epidermal growth factor receptor system(EGF-R, ErbB-1). Neuregulins consist of a large familyof proteins arising from alternative mRNA splicing ofa single gene located at 8p22-p11. Activation ofErbB-2 by neuregulins occurs in heterodimeric complexes withErbB-3 and ErbB-4. A panel of human gliomacell lines, which had previously been analyzed forErbB-2 expression, was examined for ErbB-3 and ErbB-4expression. Coordinate expression of ErbB-2, -3 or -4was not observed in these cell lines. Despitethe presence of a complete system capable ofsignaling in about half the cell lines, noconstitutive activation of ErbB-2, -3 or -4 wasobserved, and autophosphorylation of ErbB-2 in response toheregulin was observed only in one cell linefrom the panel, NCE-G84. Moreover, the addition ofrecombinant heregulin or antibodies capable of disrupting ErbB-2/ErbB-3complexes had no effect on cell proliferation. Weconclude that the role of neuregulins and itsreceptors in the control of glioma cell proliferationmay be limited or may be context dependenton in situ conditions which are lost invitro. Alternatively, neuregulins may be involved in celldifferentiation or survival in the central nervous system.Data supporting these conclusions are described in moredetail herein.