title: ErbB-3 mediates differential mitogenic effects of NDF/heregulin isoforms on mouse keratinocytes.
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.
authors.affiliation: Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Marikovsky
authors.forename: S
authors.initials: S
authors.lastname: Lavi
authors.forename: R
authors.initials: R
authors.lastname: Pinkas-Kramarski
authors.forename: D
authors.initials: D
authors.lastname: Karunagaran
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Wen
authors.forename: Y
authors.initials: Y
authors.lastname: Yarden
mesh_terms: 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
chemical_list: 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