MICAL2 Promotes Breast Cancer Cell Migration by Maintaining EGFR Stability and EGFR/P38 Signaling Activation.

MICAL2, a cytoskeleton dynamics regulator, is identified associated with survival and metastasis of several types of cancers recently. The present study was designed to investigate the role of MICAL2 in breast cancer cell migration as well as its underlying mechanisms.The relationship between MICAL2 and EGF/EGFR signaling was analyzed by using gene overexpression and knockdown techniques. Cell migration was measured by wound healing assays. Activation of EGF/EGFR singaling pathways were evaluated by immunofluorescence, qPCR, Western blotting and zymography techniques. Rac1 activity was assessed by pulldown assay. Correlation of MICAL2 and EGFR in breast cancer specimens was examined by using immunohistochemical analysis.Ectopic expression of MICAL2 in MCF-7 cells augmented EGFR protein level, accompanied by the promotion of cell migration. Silencing MICAL2 in MDA-MB-231 cells destabilized EGFR and inhibited cell migration. In mechanism, the maintaining effect of MICAL2 on EGFR protein content was due to a delay in EGFR degradation. Expression of MICAL2 was also shown positively correlated with the activation of P38/HSP27 and P38/MMP9 signalings, which are the main downstream signaling cascades of EGF/EGFR involved in cell migration. Further analysis indicated that Rac1 activation contributed to the maintaining effect of MICAL2 on EGFR stability. In addition, analysis of breast cancer specimens revealed a positive correlation between MICAL2 and EGFR levels and an association between MICAL2 expression and worse prognosis.MICAL2 is a major regulator of breast cancer cell migration, maintaining EGFR stability and subsequent EGFR/P38 signaling activation through inhibiting EGFR degradation in a Rac1-dependent manner. This article is protected by copyright. All rights reserved.