Different modes of endothelial-smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions
Different modes of endothelial-smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions
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DOI：
10.1073/pnas.1323761111
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发表时间：
2014-02-04
影响因子：
11.1
通讯作者：
Chiu, Jeng-Jiann
中科院分区：
文献类型：
--
作者：
Chang, Shun-Fu;Chen, Li-Jing;Chiu, Jeng-Jiann
β -catenin磷酸化在调节其功能中起重要作用，但不同形式的β -catenin磷酸化对异细胞相互作用的影响尚不清楚。在这里，我们研究了内皮细胞（ECs）和平滑肌细胞（SMCs）之间的异细胞相互作用是否可以触发vcatenin磷酸化的不同模式，以及随之而来的EC功能调节。ECs与SMCs共培养，开始直接接触和旁分泌相互作用。EC- smc共培养同时诱导了EC β -连环蛋白在细胞质/细胞核和细胞膜上酪氨酸142位点（Tyr142）和丝氨酸45/苏氨酸41位点（Ser45/Thr41）的磷酸化。用smc条件培养基处理ECs可诱导β -连环蛋白仅在Ser45/Thr41位点磷酸化。这些结果表明，EC-SMC共培养的不同磷酸化作用分别通过异细胞直接接触和旁分泌作用诱导。利用特异性阻断肽、拮抗剂和sirna，我们发现β -catenin tyr142磷酸化是由连接蛋白43/Fer介导的，β -catenin Ser45/ thr41磷酸化是由smc释放的骨形态发生蛋白通过VE-cadherin和骨形态发生蛋白受体ii /Smad5介导的。用β - catenintyr142或-Ser45突变体转染EC表明，这两种磷酸化形式的β -catenin调节EC的差异功能：tyr142磷酸化的β -catenin刺激血管细胞粘附分子-1表达，增加EC单核细胞粘附，但Ser45/ thr41磷酸化的β -catenin减弱ve -cadherin依赖的连接结构，增加EC的通透性。我们的研究结果为理解EC-SMC相互作用下β -catenin不同磷酸化模式的调控复杂性提供了新的见解，并表明β -catenin的不同磷酸化形式通过不同的异细胞相互作用在血管病理生理调节中发挥重要作用。
beta-Catenin phosphorylation plays important roles in modulating its functions, but the effects of different phosphorylated forms of beta-catenin in response to heterocellular interaction are unclear. Here we investigated whether distinct modes of phosphorylation on vcatenin could be triggered through heterocellular interactions between endothelial cells (ECs) and smooth muscle cells (SMCs), and the consequent modulation of EC functions. ECs were cocultured with SMCs to initiate direct contact and paracrine interaction. EC-SMC coculture induced EC beta-catenin phosphorylations simultaneously at tyrosine 142 (Tyr142) and serine 45/threonine 41 (Ser45/Thr41) at the cytoplasm/nuclei and the membrane, respectively. Treating ECs with SMC-conditional medium induced beta-catenin phosphorylation only at Ser45/Thr41. These findings indicate that different phosphorylation effects of EC-SMC coculture were induced through heterocellular direct contact and paracrine effects, respectively. Using specific blocking peptides, antagonists, and siRNAs, we found that the beta-catenin Tyr142-phosphorylation was mediated by connexin 43/Fer and that the beta-catenin Ser45/Thr41-phosphorylation was mediated by SMC-released bone morphogenetic proteins through VE-cadherin and bone morphogenetic protein receptor-II/Smad5. Transfecting ECs with beta-cateninTyr142 or -Ser45 mutants showed that these two phosphorylated forms of beta-catenin modulate differential EC function: The Tyr142phosphorylated beta-catenin stimulates vascular cell-adhesion molecule-1 expression to increase EC-monocytic adhesion, but the Ser45/Thr41-phosphorylated beta-catenin attenuates VE-cadherin-dependent junction structures to increase EC permeability. Our findings provide new insights into the understanding of regulatory complexities of distinct modes of beta-catenin phosphorylations under EC-SMC interactions and suggest that different phosphorylated forms of beta-catenin play important roles in modulating vascular pathophysiology through different heterocellular interactions.