HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4.

Strunk KE, Husted C, Miraglia LC, Sandahl M, Rearick WA, Hunter DM, Earp HS, Muraoka-Cook RS
Cancer Res. 2007 67 (14): 6582-90

PMID: 17638867 · PMCID: PMC2917069 · DOI:10.1158/0008-5472.CAN-06-4145

Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80(HER4), containing nuclear localization sequences) and results in G(2)-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 G(2)-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.

MeSH Terms (16)

Amino Acid Motifs Antigens, Polyomavirus Transforming Cell Division Cell Line, Transformed Cell Line, Tumor Cell Nucleus ErbB Receptors G2 Phase Green Fluorescent Proteins HeLa Cells Humans Mitosis Neuregulin-1 Protein Structure, Tertiary Receptor, ErbB-4 Ubiquitin

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