QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 17, Issue 9, 4118-4129, September 2006

This Article Full Text Full Text (PDF) All Versions of this Article: E06-02-0101v1 17/9/4118    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Muraoka-Cook, R. S. Articles by Earp, H. S. Search for Related Content PubMed PubMed Citation Articles by Muraoka-Cook, R. S. Articles by Earp, H. S., III

The Intracellular Domain of ErbB4 Induces Differentiation of Mammary Epithelial Cells

Rebecca S. Muraoka-Cook^*,, Melissa Sandahl^*, Carty Husted^*, Debra Hunter^*, Leah Miraglia^*, Shu-mang Feng^*, Klaus Elenius, and H. Shelton Earp, III^*,,||

*Lineberger Comprehensive Cancer Center and Departments of Genetics, Medicine, and ^||Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and Medicity Research Laboratory and Departments of Medical Biochemistry and Molecular Biology and Oncology, University of Turku, FI-20520, Turku, Finland

Submitted February 6, 2006; Revised June 13, 2006; Accepted July 5, 2006
Monitoring Editor: Carl-Henrik Heldin

Differentiation of mammary epithelium in vivo requires signaling through prolactin- and ErbB4/HER4-dependent mechanisms; how these pathways intersect is unknown. We show herein that HC11 mouse mammary cells undergo ErbB4-dependent lactational differentiation. Prolactin and the ErbB4 ligand HB-EGF each induced STAT5A activation, expression of lactogenic differentiation markers, and lumen formation in three-dimensional Matrigel cultures in HC11 cells. ErbB4 undergoes ligand-dependent transmembrane domain cleavage at Val-675, releasing a soluble 80-kDa intracellular domain (s80^HER4) that localizes to nuclei; the physiological relevance of s80^HER4 is unknown. A HER4^V675A mutant abolishing transmembrane cleavage impaired STAT5A activity, lactogenic gene expression, and lumen formation. Kinase-dead HER4^KD was neither cleaved nor able to induce differentiation of HC11 cells. Without treating HC11 cells with prolactin or HB-EGF, s80^HER4 (expressed from a cDNA construct) localized to the nucleus, activated STAT5A, and induced three-dimensional lumen formation. Nuclear localization of exogenous s80^HER4 required intact kinase activity of s80^HER4, as did activation of STAT5A. In contrast, nuclear localization of s80^HER4 and STAT5A activation did not require the 16-amino acid region of the ErbB4 intracellular domain specific to the Cyt-1 isoform of ErbB4, and absent in the Cyt-2 isoform. These results suggest that s80^HER4 formation contributes to ErbB4-dependent differentiation of mammary epithelial cells.

Address correspondence to: H. Shelton Earp (hse{at}med.unc.edu)

Abbreviations used: EGF, epidermal growth factor; HB-EGF, heparin-binding EGF-like growth factor; PRL, prolactin; TACE, tumor necrosis factor- converting enzyme; PBS, phosphate-buffered saline; RLU, relative light units; RT-PCR, reverse transcription polymerase chain reaction

This article has been cited by other articles:

				A. Naresh, A. D. Thor, S. M. Edgerton, K. C. Torkko, R. Kumar, and F. E. Jones The HER4/4ICD Estrogen Receptor Coactivator and BH3-Only Protein Is an Effector of Tamoxifen-Induced Apoptosis Cancer Res., August 1, 2008; 68(15): 6387 - 6395. [Abstract] [Full Text] [PDF]

				F. Zeng, M.-Z. Zhang, A. B. Singh, R. Zent, and R. C. Harris ErbB4 Isoforms Selectively Regulate Growth Factor induced Madin-Darby Canine Kidney Cell Tubulogenesis Mol. Biol. Cell, November 1, 2007; 18(11): 4446 - 4456. [Abstract] [Full Text] [PDF]

				S.-M. Feng, C. I. Sartor, D. Hunter, H. Zhou, X. Yang, L. S. Caskey, R. Dy, R. S. Muraoka-Cook, and H. S. Earp III The HER4 Cytoplasmic Domain, But Not Its C Terminus, Inhibits Mammary Cell Proliferation Mol. Endocrinol., August 1, 2007; 21(8): 1861 - 1876. [Abstract] [Full Text] [PDF]

				K. E. Strunk, C. Husted, L. C. Miraglia, M. Sandahl, W. A. Rearick, D. M. Hunter, H. S. Earp III, and R. S. Muraoka-Cook HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80HER4 Cancer Res., July 15, 2007; 67(14): 6582 - 6590. [Abstract] [Full Text] [PDF]