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HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80^HER4

¹ UNC Lineberger Comprehensive Cancer Center and the Departments of ² Medicine, ³ Pharmacology, and ⁴ Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Requests for reprints: Rebecca S. Muraoka-Cook, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, 102 Mason Farm Road, Chapel Hill, NC 27599. Phone: 919-966-1573; Fax: 919-966-3015; E-mail: rebecca_cook{at}med.unc.edu.

Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80^HER4, containing nuclear localization sequences) and results in G₂-M delay by unknown signaling mechanisms. We report herein that s80^HER4 contains a functional cyclin B–like sequence known as a D-box, which targets proteins for degradation by anaphase-promoting complex (APC)/cyclosome, a multisubunit ubiquitin ligase. s80^HER4 ubiquitination and proteasomal degradation occurred during mitosis but not during S phase. Inhibition of an APC subunit (APC2) using short interfering RNA knockdown impaired s80^HER4 degradation. Mutation of the s80^HER4 D-box sequence stabilized s80^HER4 during mitosis, and s80^HER4-dependent growth inhibition via G₂-M delay was significantly greater with the D-box mutant. Polyomavirus middle T antigen–transformed HC11 cells expressing s80^HER4 resulted in smaller, less proliferative, more differentiated tumors in vivo than those expressing kinase-dead s80^HER4 or the empty vector. Cells expressing s80^HER4 with a disrupted D-box did not form tumors, instead forming differentiated ductal structures. These results suggest that cell cycle–dependent degradation of s80^HER4 limits its growth-inhibitory action, and stabilization of s80^HER4 enhances tumor suppression, thus providing a link between HER4-mediated growth inhibition and cell cycle control. [Cancer Res 2007;67(14):6582–90]

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