p300/-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)
p300/-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)
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DOI：
10.1074/jbc.m115.706416
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发表时间：
2016-03-18
影响因子：
4.8
通讯作者：
Borok, Zea
中科院分区：
文献类型：
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作者：
Rieger, Megan E.;Zhou, Beiyun;Borok, Zea
在正常周转和修复过程中，维持组织稳态需要干细胞/祖细胞-子代关系的维持。 Wnt 信号传导与成体干细胞/祖细胞的维持和分化有关，但该通路如何发挥这些二分作用仍然是个谜。我们之前提出了一个模型，表明β-连环蛋白与同源Kat3共激活剂、p300或CREB结合蛋白的特异性相互作用，差异性地调节胚胎干细胞的维持与分化。对驱动差异-连环蛋白/共激活剂相互作用的内源机制及其在成体干细胞/祖细胞维持与分化中的作用的了解有限，这促使我们在成体祖细胞分化的确定模型中探索这一过程。我们主要关注 II 型肺泡上皮 (AT2) 细胞（远端肺上皮的祖细胞），并确定了一个新的轴，WNT5a/蛋白激酶 C (PKC) 信号通过该轴调节特定的 β-连环蛋白/共激活剂相互作用，以促进成体祖细胞分化。随着 AT2 细胞分化为 I 型 (AT1) 细胞样表型，p300/-连环蛋白相互作用增强，但 CBP/-连环蛋白相互作用增强。此外，p300 转录激活 AT1 细胞特异性基因 Aqp-5。 IQ-1 是 p300/-catenin 相互作用的特异性抑制剂，不仅可以防止原代 AT2 细胞的分化，还可以防止气管上皮细胞和 C2C12 成肌细胞的分化。 p300 Ser-89 磷酸化增强了 p300/-catenin 相互作用，同时发生肺泡上皮细胞分化。 WNT5a 是一种传统的非经典 WNT 配体，以 PKC 依赖性方式调节 Ser-89 磷酸化和 p300/-连环蛋白相互作用，可能涉及 PKC。这些研究确定了成体祖细胞分化中经典和非经典 Wnt 信号传导的新交叉点，这对于靶向 β-catenin 调节成体祖细胞在疾病中的行为具有重要意义。
Maintenance of stem/progenitor cell-progeny relationships is required for tissue homeostasis during normal turnover and repair. Wnt signaling is implicated in both maintenance and differentiation of adult stem/progenitor cells, yet how this pathway serves these dichotomous roles remains enigmatic. We previously proposed a model suggesting that specific interaction of -catenin with either of the homologous Kat3 co-activators, p300 or CREB-binding protein, differentially regulates maintenance versus differentiation of embryonic stem cells. Limited knowledge of endogenous mechanisms driving differential -catenin/co-activator interactions and their role in adult somatic stem/progenitor cell maintenance versus differentiation led us to explore this process in defined models of adult progenitor cell differentiation. We focused primarily on alveolar epithelial type II (AT2) cells, progenitors of distal lung epithelium, and identified a novel axis whereby WNT5a/protein kinase C (PKC) signaling regulates specific -catenin/co-activator interactions to promote adult progenitor cell differentiation. p300/-catenin but not CBP/-catenin interaction increases as AT2 cells differentiate to a type I (AT1) cell-like phenotype. Additionally, p300 transcriptionally activates AT1 cell-specific gene Aqp-5. IQ-1, a specific inhibitor of p300/-catenin interaction, prevents differentiation of not only primary AT2 cells, but also tracheal epithelial cells, and C2C12 myoblasts. p300 phosphorylation at Ser-89 enhances p300/-catenin interaction, concurrent with alveolar epithelial cell differentiation. WNT5a, a traditionally non-canonical WNT ligand regulates Ser-89 phosphorylation and p300/-catenin interactions in a PKC-dependent manner, likely involving PKC. These studies identify a novel intersection of canonical and non-canonical Wnt signaling in adult progenitor cell differentiation that has important implications for targeting -catenin to modulate adult progenitor cell behavior in disease.