Open AccessTyrosine phosphorylation of S1PR1 leads to chaperone BiP-mediated import to the endoplasmic reticulum
Author(s) -
Mumtaz Anwar,
Ruhul Amin,
Vijay Avin Balaji Ragunathrao,
Jacob Matsche,
Andrei V. Karginov,
Richard D. Minshall,
Gary Mo,
Yulia Komarova,
Dolly Mehta
Publication year - 2021
Publication title -
the journal of cell biology/the journal of cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.414
H-Index - 380
eISSN - 1540-8140
pISSN - 0021-9525
DOI - 10.1083/jcb.202006021
Subject(s) - s1pr1 , phosphorylation , biology , microbiology and biotechnology , g protein coupled receptor , endoplasmic reticulum , tyrosine phosphorylation , signal transduction , cancer research , vascular endothelial growth factor a , vascular endothelial growth factor , vegf receptors
Cell surface G protein–coupled receptors (GPCRs), upon agonist binding, undergo serine–threonine phosphorylation, leading to either receptor recycling or degradation. Here, we show a new fate of GPCRs, exemplified by ER retention of sphingosine-1-phosphate receptor 1 (S1PR1). We show that S1P phosphorylates S1PR1 on tyrosine residue Y143, which is associated with recruitment of activated BiP from the ER into the cytosol. BiP then interacts with endocytosed Y143-S1PR1 and delivers it into the ER. In contrast to WT-S1PR1, which is recycled and stabilizes the endothelial barrier, phosphomimicking S1PR1 (Y143D-S1PR1) is retained by BiP in the ER and increases cytosolic Ca2+ and disrupts barrier function. Intriguingly, a proinflammatory, but non-GPCR agonist, TNF-α, also triggered barrier-disruptive signaling by promoting S1PR1 phosphorylation on Y143 and its import into ER via BiP. BiP depletion restored Y143D-S1PR1 expression on the endothelial cell surface and rescued canonical receptor functions. Findings identify Y143-phosphorylated S1PR1 as a potential target for prevention of endothelial barrier breakdown under inflammatory conditions.