The heregulin/human epidermal growth factor receptor as a new growth factor system in melanoma with multiple ways of deregulation.
In a screening for new growth factors released by melanoma cells, we found that the p185-phosphorylating capacity of a medium conditioned by a melanoma cell line was due to the secretion of heregulin, a ligand for the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Expression of heregulin, including a new isoform, and secretion of functionally active protein was found in several cell lines. Receptor activation by heregulin, either autocrine or paracrine, resulted in a potent growth stimulation of both melanocytes and melanoma cells. Heregulin receptor HER3 and coreceptor HER2 were the main receptors expressed by these cells. Nevertheless, none of the cell lines in our panel overexpressed HER2 or HER3. In contrast, loss of HER3 was found in two cell lines, whereas one cell line showed loss of functional HER2, both types of deregulations resulting in unresponsiveness to heregulin. This implies the heregulin/HER system as a possible important physiologic growth regulatory system in melanocytes in which multiple deregulations may occur during progression toward melanoma, all resulting in, or indicating, growth factor independence.
Stove
Christophe
C
Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine, Ghent University Hospital, Ghent, Belgium.
Stove
Veronique
V
Derycke
Lara
L
Van Marck
Veerle
V
Mareel
Marc
M
Bracke
Marc
M
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019898:Autocrine Communication; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects; D008545:Melanoma; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019899:Paracrine Communication; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D012878:Skin Neoplasms
D066246:ErbB Receptors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3