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Signaling and Regulation

Heregulins Implicated in Cellular Functions Other Than Receptor Activation

Molecular Tumorbiology Unit, Department of Research, Stiftung Tumorbank and University Clinics Medical School, Basel, Switzerland

Requests for reprints: Madlaina Breuleux, Novartis Pharma AG, Klybeckstrasse 125, WKL-125.12.59, 4002 Basel, Switzerland. Phone: 41-61-696-25-17; Fax: 41-61-696-63-81. E-mail: madlaina.breuleux{at}novartis.com

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 HRG_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 HRG in a yeast two-hybrid system, and coimmunoprecipitation of endogenous HRG was done. The data reveal positive interactions of HRG_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, HRG_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. (Mol Cancer Res 2006;4(1):27–37)

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