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: As Erk1/2 signaling increases the nuclear accumulation of unphosphorylated (active) β-catenin (Chang et al., 2011), and because Pin1 also has a similar effect on β-catenin in breast cancer cells (Ryo et al., 2001), we examined whether Pin1/Rab2A/p-Erk signaling regulates nuclear β-catenin levels. Confocal analysis showed that most unphosphorylated β-catenin localized at the plasma membrane in starved HMLE cells but translocated into the nucleus, along with increased p-Erk1/2 6 hr after EGF stimulation (Figure 5A). However, in Rab2A-overexpressing and Pin1-overexpressing cells, not only was p-Erk1/2 obviously increased but also unphosphorylated β-catenin was readily detected in the nucleus as early as 2 hr and accumulated further with time after EGF stimulation (Figures 5B and 5C). In contrast, in Rab2A or Pin1 KD cells, not only was p-Erk1/2 not increased but also nuclear unphosphorylated β-catenin was hardly detectable even 6 hr after stimulation (Figures 5D and 5G). Notably, overexpression of Rab2A in Pin1 KD cells caused Erk1/2 activation and nuclear translocation and, importantly, unphosphorylated β-catenin localization to the nucleus (Figure 5E). Conversely, Rab2A KD in Pin1-overexpressing cells prevented Erk1/2 activation and nuclear translocation of unphosphorylated β-catenin (Figure 5F). Western blot analysis with nuclear fraction further confirmed these results (Figure 5H). These data together support a model in which the Pin1/Rab2A/Erk1/2 pathway activates β-catenin.
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.