Activation of Intracellular Calcium by Multiple Wnt Ligands and Translocation of beta-Catenin into the Nucleus A CONVERGENT MODEL OF Wnt Ca2+ AND Wnt/beta-CATENIN PATHWAYS

作者：Thrasivoulou Christopher; Millar Michael; Ahmed Aamir^*

来源：Journal of Biological Chemistry, 2013, 288(50): 35651-35659.

DOI：10.1074/jbc.M112.437913

• Beta-Catenin
• Calcium Signaling
• Cell Signaling
• Nuclear Membrane
• Wnt Signaling
• Canonical and Non-canonical Signaling
• Intranuclear Calcium
• Macromolecular Transport
• Nuclear Membrane Potential

Background: Cellular transducers of Wnt signaling, -catenin and Ca2+, are considered to act via independent canonical and non-canonical pathways. Results: Six Wnt ligands activated cytosolic and intranuclear Ca2+ and nuclear translocation of -catenin. Conclusion: Wnt -catenin and Ca2+ signaling are coupled in mammalian cells. Significance: A coupled model of Wnt/Ca2+ and -catenin signaling that challenges the canonical and non-canonical categorization is proposed.
Ca2+ and -catenin, a 92-kDa negatively charged transcription factor, transduce Wnt signaling via the non-canonical, Wnt/Ca2+ and canonical, Wnt/-catenin pathways independently. The nuclear envelope is a barrier to large protein entry, and this process is regulated by intracellular calcium [Ca2+](i) and trans-nuclear potential. How -catenin traverses the nuclear envelope is not well known. We hypothesized that Wnt/Ca2+ and Wnt/-catenin pathways act in a coordinated manner and that [Ca2+](i) release facilitates -catenin entry into the nucleus in mammalian cells. In a live assay using calcium dyes in PC3 prostate cancer cells, six Wnt peptides (3A, 4, 5A, 7A, 9B, and 10B) mobilized [Ca2+](i) but Wnt11 did not. Based upon dwell time (range = 15-30 s) of the calcium waveform, these Wnts could be classified into three classes: short, 3A and 5A; long, 7A and 10B; and very long, 4 and 9B. Wnt-activated [Ca2+](i) release was followed by an increase in intranuclear calcium and the depolarization of both the cell and nuclear membranes, determined by using FM4-64. In cells treated with Wnts 5A, 9B, and 10B, paradigm substrates for each Wnt class, increased [Ca2+](i) was followed by -catenin translocation into the nucleus in PC3, MCF7, and 253J, prostate, breast, and bladder cancer cell lines; both the increase in Wnt 5A, 9B, and 10B induced [Ca2+](i) release and -catenin translocation are suppressed by thapsigargin in PC3 cell line. We propose a convergent model of Wnt signaling network where Ca2+ and -catenin pathways may act in a coordinated, interdependent, rather than independent, manner.

• 出版日期2013-12-13