ErbB-3 mediates differential mitogenic effects of NDF/heregulin isoforms on mouse keratinocytes.
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.
Marikovsky
M
M
Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Lavi
S
S
Pinkas-Kramarski
R
R
Karunagaran
D
D
Liu
N
N
Wen
D
D
Yarden
Y
Y
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D006023:Glycoproteins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology*; D008969:Molecular Sequence Data; D020880:Neuregulins; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D006023:Glycoproteins; D008934:Mitogens; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4