Adapter Protein RapGEF1 Is Required for ERK1/2 Signaling in Response to Elevated Phosphate in Vascular Smooth Muscle Cells.

Autor:	Chavkin NW; Department of Bioengineering, University of Washington, Seattle, Washington, USA., Leaf EM; Department of Bioengineering, University of Washington, Seattle, Washington, USA., Brooks KE; Department of Bioengineering, University of Washington, Seattle, Washington, USA., Wallingford MC; Department of Bioengineering, University of Washington, Seattle, Washington, USA., Lund SM; Department of Bioengineering, University of Washington, Seattle, Washington, USA., Giachelli CM; Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Jazyk:	angličtina
Zdroj:	Journal of vascular research [J Vasc Res] 2021; Vol. 58 (5), pp. 277-285. Date of Electronic Publication: 2021 May 05.
DOI:	10.1159/000516044
Abstrakt:	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 an 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 VSMCs. Knockdown of RapGEF1 and small molecule inhibitors against Rap1, B-Raf, and Mek1/2 eliminated elevated Pi-induced ERK1/2 phosphorylation. Knockdown of RapGEF1 inhibited SM22α mRNA expression and blocked elevated Pi-induced downregulation 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. (© 2021 S. Karger AG, Basel.)
Databáze:	MEDLINE
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