The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation.
Bottom Line: Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation.Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients.Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.
Affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.Show MeSH
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Mentions: To elucidate how Rab2A overexpression or its Q58H mutation activates Erk1/2, we first examined whether Rab2A co-localized with Erk1/2. Overexpressing WT Rab2A not only activated Erk1/2 but also surprisingly colocalized with activated Erk1/2 at the perinuclear region at 5 min (Figure 4A) and 1 hr (Figure S4A) after EGF stimulation. Overexpressing Rab2A Q58H at levels similar to the endogenous level also activated and colocalized with Erk1/2 (Figures 4A and S4A). Importantly, Rab2A and its Q58H mutant colocalized with Erk1/2 at the ERGIC, as assayed by ERGIC53 staining (Figure 4B). To examine whether Rab2A’s vesicular trafficking function is associated with Erk activation, we used brefeldin A (BFA) to block the trafficking from the ERGIC to ER. As shown previously (Hauri et al., 2000), BFA treatment damaged the ERGIC structure (Figure S4B) but did not obviously affect Erk phosphorylation (Figure S4C), suggesting that Erk1/2 activation is likely to be independent of Rab2A’s trafficking function.
Affiliation: Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.