ErbB-3 mediates differential mitogenic effects of NDF/heregulin isoforms on mouse keratinocytes
Marikovsky, M.; Lavi, S.; Pinkas-Kramarski, R.; Karunagaran, D.; Liu, N.; Wen, D.; Yarden, Y.
Oncogene 10(7): 1403-1411
1995
ISSN/ISBN: 0950-9232 PMID: 7731691 Document Number: 443835
The family of Neu differentiation factors (NDFs, or heregulins) includes a dozen secreted glycoproteins, whose receptor binding domain displays two variants, a and beta, and they bind to two receptor tyrosine kinases, ErbB-3 and ErbB-4. Certain isoforms were reported to induce growth-arrest and differentiation of mammary tumor cells, while other breast cancer cell lines responded mitogenically. The present study addressed the biologic effects of various NDF isoforms on normal EGF-dependent epithelial cells, Balb/MK keratinocytes, that can undergo either proliferation or differentiation. We found that beta isoforms of NDF induced a mitogenic effect, that was significantly smaller than the maximal response to EGF. By contrast with NDF-beta, NDF-alpha isoforms exerted almost no mitogenic effect, but they were sufficient to maintain keratinocytes in culture. Consistent with their higher mitogenic potency, NDF-beta isoforms bound to Balb/MK cells with higher affinity (K-d=2.2 nM) than alpha isoforms, however both groups shared their receptor, that we identified as ErbB-3. No transcript of ErbB4 was detectable in the keratinocytes, but these cells express multiple NDF mRNAs and also ErbB-2. We conclude that different isoforms of NDF induce distinct growth regulatory effects on cultured keratinocytes, through direct interaction with ErbB-3.