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ErbB-3 mediates differential mitogenic effects of NDF/heregulin isoforms on mouse keratinocytes
M Marikovsky1, S Lavi, R Pinkas-Kramarski
1Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
The family of Neu differentiation factors (NDFs, or heregulins) includes a dozen secreted glycoproteins, whose receptor binding domain displays two variants, alpha 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 (Kd = 2.2 nM) than alpha isoforms, however both groups shared their receptor, that we identified as ErbB-3. No transcript of ErbB-4 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.
Insights
Neu differentiation factors (NDFs) exhibit distinct effects on epithelial cells. NDF-beta isoforms promote proliferation, while NDF-alpha isoforms maintain cell survival, both interacting via the ErbB-3 receptor.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Neu differentiation factors (NDFs), also known as heregulins, are secreted glycoproteins with alpha and beta receptor binding domain variants.
- NDFs bind to receptor tyrosine kinases ErbB-3 and ErbB-4, influencing mammary tumor cell growth and differentiation.
- Previous studies show varied responses of breast cancer cell lines to different NDF isoforms.
Purpose of the Study:
- To investigate the distinct biological effects of various NDF isoforms on normal EGF-dependent epithelial cells (Balb/MK keratinocytes).
- To determine the specific receptor interactions and signaling pathways involved in NDF-mediated keratinocyte responses.
Main Methods:
- Cultured Balb/MK keratinocytes were treated with different NDF isoforms (alpha and beta).
- Mitogenic responses and cell maintenance were assessed.
- Receptor binding affinity and receptor expression (ErbB-3, ErbB-4, ErbB-2) were analyzed.
Main Results:
- NDF-beta isoforms induced a significant mitogenic effect, though less potent than EGF.
- NDF-alpha isoforms showed minimal mitogenic activity but were sufficient for keratinocyte maintenance.
- NDF-beta isoforms bound to Balb/MK cells with higher affinity (Kd = 2.2 nM) than NDF-alpha isoforms, with both interacting via ErbB-3.
Conclusions:
- Different NDF isoforms exert distinct growth regulatory effects on cultured keratinocytes.
- These effects are mediated through direct interaction with the ErbB-3 receptor.
- Keratinocytes express NDF mRNAs and ErbB-2, but not ErbB-4, highlighting specific signaling pathways.