Adapter Protein RapGEF1 Is Required for ERK1/2 Signaling in Response to Elevated Phosphate in Vascular Smooth Muscle Cells.
Adapter Protein RapGEF1 Is Required for ERK1/2 Signaling in Response to Elevated Phosphate in Vascular Smooth Muscle Cells.
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DOI：
10.1159/000516044
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发表时间：
2021
影响因子：
1.7
通讯作者：
Giachelli CM
中科院分区：
文献类型：
--
作者：
Chavkin NW;Leaf EM;Brooks KE;Wallingford MC;Lund SM;Giachelli CM
钠依赖性磷酸盐转运蛋白SLC 20 A1是无机磷（Pi）升高诱导的血管平滑肌细胞（VSMC）基质矿化和表型转分化所必需的。最近，高Pi显示通过SLC 20 A1通过Pi摄取独立功能在VSMC中诱导ERK 1/2磷酸化，表明细胞对高Pi的信号传导应答。先前的研究发现Rap 1鸟嘌呤核苷酸交换因子（RapGEF 1）是一种与SLC 20 A1相互作用的蛋白质，RapGEF 1通过Rap 1的激活促进ERK 1/2的磷酸化。在这项研究中，我们测试的假设，RapGEF 1是SLC 20 A1介导的PI诱导的ERK 1/2磷酸化途径的关键组成部分。研究了SLC 20 A1和RapGEF 1的共定位、用siRNA敲减RapGEF 1以及Rap 1、B-Raf和Mek 1/2的小分子抑制剂。SLC 20 A1和RapGEF 1共定位于血管平滑肌细胞的膜周结构。RapGEF 1和针对Rap 1、B-Raf和Mek 1/2的小分子抑制剂的敲低消除了Pi诱导的ERK 1/2磷酸化升高。RapGEF 1的敲低抑制了SM 22 α mRNA的表达，并阻断了Pi诱导的SM 22 α mRNA的下调。总之，这些数据表明，RapGEF 1是通过Rap 1/B-Raf/Mek 1/2细胞信号传导途径，从而促进ERK 1/2磷酸化并抑制VSMC中SM 22 α基因表达的SLC 20 a1介导的Pi信号传导升高所必需的。
The sodium-dependent phosphate transporter, SLC20A1, is required for elevated inorganic phosphate (Pi) induced vascular smooth muscle cell (VSMC) matrix mineralization and phenotype transdifferentiation. Recently, elevated Pi was shown to induce ERK1/2 phosphorylation through SLC20A1 by Pi-uptake independent functions in VSMCs, suggesting a cell signaling response to elevated Pi. Previous studies identified Rap1 guanine nucleotide exchange factor (RapGEF1) as a SLC20A1 interacting protein, and RapGEF1 promotes ERK1/2 phosphorylation through Rap1 activation. In this study, we tested the hypothesis that RapGEF1 is a critical component of the SLC20A1-mediated Pi-induced ERK1/2 phosphorylation pathway. Co-localization of SLC20A1 and RapGEF1, knockdown of RapGEF1 with siRNA, and small molecule inhibitors of Rap1, B-Raf, and Mek1/2 were investigated. SLC20A1 and RapGEF1 were co-localized in peri-membranous structures in vascular smooth muscle cells. Knock-down of RapGEF1 and small molecule inhibitors against Rap1, B-Raf, and Mek1/2 eliminated elevated Pi-induced ERK1/2 phosphorylation. Knock-down of RapGEF1 inhibited SM22α mRNA expression and blocked elevated Pi-induced down-regulation of SM22α mRNA. Together, these data suggest that RapGEF1 is required for SLC20a1-mediated elevated Pi signaling through a Rap1/B-Raf/Mek1/2 cell signaling pathway thereby promoting ERK1/2 phosphorylation and inhibiting SM22α gene expression in VSMCs.
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影响因子：
20.3
作者：
Arai, A;Nosaka, Y;Miura, O
通讯作者：
Miura, O
影响因子：
20.1
作者：
Li, XW;Yang, HY;Giachelli, CM
通讯作者：
Giachelli, CM
影响因子：
5.3
作者：
Wang, ZP;Dillon, TJ;Stork, PJS
通讯作者：
Stork, PJS
影响因子：
4.8
作者：
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通讯作者：
Beck, Laurent
影响因子：
4
作者：
Speer, Mei Y.;Li, Xianwu;Hiremath, Pranoti G.;Giachelli, Cecilia M.
通讯作者：
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