Cullin-3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2-positive breast cancer cells
| Autor: | Tomohiko Taguchi, Masashi Maekawa, Yasutsugu Takada, Shigeki Higashiyama, Katsuhisa Kawai, Yoshiaki Kamei, Jun Nakayama, Akari Murakami, Kentaro Semba, Nobukazu Araki |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
rac1 GTP-Binding Protein Cancer Research membrane ruffle Receptor ErbB-2 RHOB RAC1 Breast Neoplasms Endosomes 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Molecular and Stem Cell Biology Epidermal growth factor Cell Line Tumor HER2 RhoB GTP-Binding Protein medicine Humans skin and connective tissue diseases rhoB GTP-Binding Protein Cell Proliferation biology Chemistry Cell growth Cell Membrane Cullin‐3 General Medicine Original Articles RhoB medicine.disease Cullin Proteins Ubiquitin ligase Protein Transport 030104 developmental biology HEK293 Cells Oncology Potassium Channels Voltage-Gated 030220 oncology & carcinogenesis biology.protein Cancer research Female Original Article Signal transduction Rac1 |
| Zdroj: | Cancer Science |
| ISSN: | 1349-7006 |
| Popis: | Rho GTPase Rac1 is a central regulator of F-actin organization and signal transduction to control plasma membrane dynamics and cell proliferation. Dysregulated Rac1 activity is often observed in various cancers including breast cancer and is suggested to be critical for malignancy. Here, we showed that the ubiquitin E3 ligase complex Cullin-3 (CUL3)/KCTD10 is essential for epidermal growth factor (EGF)-induced/human epidermal growth factor receptor 2 (HER2)-dependent Rac1 activation in HER2-positive breast cancer cells. EGF-induced dorsal membrane ruffle formation and cell proliferation that depends on both Rac1 and HER2 were suppressed in CUL3- or KCTD10-depleted cells. Mechanistically, CUL3/KCTD10 ubiquitinated RhoB for degradation, another Rho GTPase that inhibits Rac1 activation at the plasma membrane by suppressing endosome-to-plasma membrane traffic of Rac1. In HER2-positive breast cancers, high expression of Rac1 mRNA significantly correlated with poor prognosis of the patients. This study shows that this novel molecular axis (CUL3/KCTD10/RhoB) positively regulates the activity of Rac1 in HER2-positive breast cancers, and our findings may lead to new treatment options for HER2- and Rac1-positive breast cancers. |
| Databáze: | OpenAIRE |
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