Abstract B14: The novel function and trafficking mechanism of nuclear ErbB-2

Abstract

We have demonstrated that ErbB-2 translocates into the nucleus through importin β1—mediated nuclear import by endosomal sorting, and transactivates transcription of cyclooxygenase-2 which has been known to be involved in tumor progression and metastasis, suggesting nuclear ErbB-2 may also contribute to the tumor malignancy. However, how the membranebound ErbB-2 can be released from the lipid bilayer and translocates into the nucleus; and the biological functions of the nuclear ErbB-2 are not yet completely understood. Here, we have identified novel ErbB-2-interacting nuclear proteins. The interplay between nuclear ErbB-2 and interacting protein was investigated, which may elucidate a novel function of nuclear ErbB-2 in contributing to tumorigenesis. In addition, ErbB-2 interacts with endoplasmic reticulum (ER) proteins, Sec61α, a subunit of Sec61 channel, and EDEM. Sec61α and EDEM are known to mediate retrotranslocation of misfolded proteins in the ER to the cytosol (called ER-associated degradation pathway). We have demonstrated that Sec61α and EDEM also play important roles in retrotranslocation of ErbB-2 to the cytosol and to the nucleus, suggesting part of ER retrotranslocation pathway is likely involved in nuclear trafficking of ErbB-2. [This work was supported by National Health Research Institutes NHRI-EX98-9603BC, National Science Council NSC952311-B-039-002 and NSC 97-3111-B-039-004 and Department of Health DOH97-TD-I-111-TM003 and DOH98-TD-I-111-TM002 (to LYL)]. Citation Information: Cancer Res 2009;69(23 Suppl):B14.