title: Heregulins implicated in cellular functions other than receptor activation.
abstract: Heregulins (HRG) are known as soluble secreted growth factors that, on binding and activating ErbB3 and ErbB4 cell surface receptors, are involved in cell proliferation, metastasis, survival, and differentiation in normal and malignant tissues. Previous studies have shown that some HRG1 splice variants are translocated to the nucleus. By investigating the subcellular localization of HRGalpha(1-241), nuclear translocation and accumulation in nuclear dot-like structures was shown in breast cancer cells. This subcellular distribution pattern depends on the presence of at least one of two nuclear localization sequences and on two domains on the HRG construct that were found to be necessary for nuclear dot formation. Focusing on the nuclear function of HRG, a mammary gland cDNA library was screened with the mature form of HRGalpha in a yeast two-hybrid system, and coimmunoprecipitation of endogenous HRG was done. The data reveal positive interactions of HRGalpha(1-241) with nuclear factors implicated in different biological functions, including transcriptional control as exemplified by interaction with the transcriptional repressor histone deacetylase 2. In addition, HRGalpha(1-241) showed transcriptional repression activity in a reporter gene assay. Furthermore, a potential of HRG proteins to form homodimers was reported and the HRG sequence responsible for dimerization was identified. These observations strongly support the notion that HRG1 splice variants have multifunctional properties, including previously unknown regulatory functions within the nucleus that are different from the activation of ErbB receptor signaling.
authors.affiliation: Novartis Pharma AG, Klybeckstrasse 125, WKL-125.12.59, 4002 Basel, Switzerland. madlaina.breuleux@novartis.com
authors.forename: Madlaina
authors.initials: M
authors.lastname: Breuleux
authors.forename: Fabrice
authors.initials: F
authors.lastname: Schoumacher
authors.forename: Daniel
authors.initials: D
authors.lastname: Rehn
authors.forename: Willy
authors.initials: W
authors.lastname: Küng
authors.forename: Heinz
authors.initials: H
authors.lastname: Mueller
authors.forename: Urs
authors.initials: U
authors.lastname: Eppenberger
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002468:Cell Physiological Phenomena; D002522:Chlorocebus aethiops; D044842:Cullin Proteins / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation / Q000235:genetics; D004815:Epidermal Growth Factor / Q000737:chemistry; D005091:Exons / Q000235:genetics; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020890:Neuregulin-1 / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D004815:Epidermal Growth Factor; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D020890:Neuregulin-1; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; C100318:Cullin 1