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The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation.

Luo ML, Gong C, Chen CH, Hu H, Huang P, Zheng M, Yao Y, Wei S, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP - Cell Rep (2015)

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.

View Article: PubMed Central - PubMed

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.

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Rab2A/p-Erk Signaling Promotes the Nuclear Translocation of Activeβ-Catenin(A and B) Rab2A promoted the nuclear translocation of unphosphorylated β-catenin (active form). HMLE cells were serum starved and then stimulated by EGF for the indicated time points.(C–E) Pin1 also promoted the nuclear translocation of unphosphorylated β-catenin and Rab2A overexpression in Pin1 KD cells rescued Erk1/2 activation and β-catenin translocation from the cell membrane to the nucleus.(F and G) Rab2A KD in Pin1-overexpressing or vector control cells inhibited p-Erk1/2 activation and β-catenin nuclear translocation. Scale bars represent 10 μm.(H) Rab2A promoted the nuclear accumulation of p-Erk1/2 and unphosphorylated β-catenin. Nuclear and total proteins were extracted after EGF stimulation following serum starvation.
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Figure 5: Rab2A/p-Erk Signaling Promotes the Nuclear Translocation of Activeβ-Catenin(A and B) Rab2A promoted the nuclear translocation of unphosphorylated β-catenin (active form). HMLE cells were serum starved and then stimulated by EGF for the indicated time points.(C–E) Pin1 also promoted the nuclear translocation of unphosphorylated β-catenin and Rab2A overexpression in Pin1 KD cells rescued Erk1/2 activation and β-catenin translocation from the cell membrane to the nucleus.(F and G) Rab2A KD in Pin1-overexpressing or vector control cells inhibited p-Erk1/2 activation and β-catenin nuclear translocation. Scale bars represent 10 μm.(H) Rab2A promoted the nuclear accumulation of p-Erk1/2 and unphosphorylated β-catenin. Nuclear and total proteins were extracted after EGF stimulation following serum starvation.

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.


The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation.

Luo ML, Gong C, Chen CH, Hu H, Huang P, Zheng M, Yao Y, Wei S, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP - Cell Rep (2015)

Rab2A/p-Erk Signaling Promotes the Nuclear Translocation of Activeβ-Catenin(A and B) Rab2A promoted the nuclear translocation of unphosphorylated β-catenin (active form). HMLE cells were serum starved and then stimulated by EGF for the indicated time points.(C–E) Pin1 also promoted the nuclear translocation of unphosphorylated β-catenin and Rab2A overexpression in Pin1 KD cells rescued Erk1/2 activation and β-catenin translocation from the cell membrane to the nucleus.(F and G) Rab2A KD in Pin1-overexpressing or vector control cells inhibited p-Erk1/2 activation and β-catenin nuclear translocation. Scale bars represent 10 μm.(H) Rab2A promoted the nuclear accumulation of p-Erk1/2 and unphosphorylated β-catenin. Nuclear and total proteins were extracted after EGF stimulation following serum starvation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401741&req=5

Figure 5: Rab2A/p-Erk Signaling Promotes the Nuclear Translocation of Activeβ-Catenin(A and B) Rab2A promoted the nuclear translocation of unphosphorylated β-catenin (active form). HMLE cells were serum starved and then stimulated by EGF for the indicated time points.(C–E) Pin1 also promoted the nuclear translocation of unphosphorylated β-catenin and Rab2A overexpression in Pin1 KD cells rescued Erk1/2 activation and β-catenin translocation from the cell membrane to the nucleus.(F and G) Rab2A KD in Pin1-overexpressing or vector control cells inhibited p-Erk1/2 activation and β-catenin nuclear translocation. Scale bars represent 10 μm.(H) Rab2A promoted the nuclear accumulation of p-Erk1/2 and unphosphorylated β-catenin. Nuclear and total proteins were extracted after EGF stimulation following serum starvation.
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.

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus