Cullin-3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2-positive breast cancer cells.

Abstract

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.

• Authors: Akari Murakami, Masashi Maekawa, Katsuhisa Kawai, Jun Nakayama, Nobukazu Araki, Kentaro Semba, Tomohiko Taguchi, Yoshiaki Kamei, Yasutsugu Takada, Shigeki Higashiyama
• Journal: Cancer science (Cancer Sci) Vol. 110 Issue 2 Pg. 650-661 (Feb 2019) ISSN: 1349-7006 [Electronic] England
• PMID: 30515933 (Publication Type: Journal Article)
• Copyright: © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Cullin Proteins
• KCTD10 protein, human
• Potassium Channels, Voltage-Gated
• RAC1 protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• rac1 GTP-Binding Protein
• rhoB GTP-Binding Protein

Topics

• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Proliferation (physiology)
• Cullin Proteins (metabolism)
• Endosomes (metabolism, physiology)
• Female
• HEK293 Cells
• Humans
• Potassium Channels, Voltage-Gated (metabolism)
• Protein Transport (physiology)
• Receptor, ErbB-2 (metabolism)
• rac1 GTP-Binding Protein (metabolism)
• rhoB GTP-Binding Protein (metabolism)