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

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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

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