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Palmitoylation is required for activated PAR1 ubiquitination and p38 MAPK signaling (1066.16)
Author(s) -
Canto Isabel,
Grimsey Neil,
Trejo JoAnn
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1066.16
Subject(s) - palmitoylation , g protein coupled receptor , microbiology and biotechnology , signal transduction , regulator of g protein signaling , biology , receptor , chemistry , mapk/erk pathway , g protein , gtpase activating protein , biochemistry , cysteine , enzyme
Palmitoylation has diverse functions in the regulation of G‐protein coupled receptor (GPCR) signaling and trafficking, yet its function in signal regulation of the protease‐activated receptor‐1 (PAR1), a GPCR for thrombin, is not known. PAR1 is a unique GPCR that couples to multiple G‐protein subtypes, but the mechanisms that regulate G‐protein selectivity are not well understood. We have previously established that PAR1 is basally palmitoylated, and regulates adaptor protein complex‐2 and ‐3 accessibility of tyrosine‐based sorting motifs within the C‐tail domain, but whether palmitoylation affects activated PAR1 G protein signaling is not known. We utilized a palmitoylation‐deficient mutant of PAR1 in which C‐tail cysteines (C387 and C388) were converted to alanines (A), to examine the role of palmitoylation on PAR1 signal regulation. In endothelial cells, palmitoylation is not critical for PAR1 recruitment to caveolar microdomains. Although the PAR1 CC/AA mutant is capable of signaling to Gq in HeLa cells, it is defective in thrombin‐induced p38 MAPK signaling. However, PAR1 CC/AA retains normal ERK1/2 signaling. Additionally, PAR1 CC/AA is defective in agonist‐induced ubiquitination, a modification that is critical for p38 MAPK signaling. Thus, palmitoylation is likely to stabilize the proper PAR1 C‐tail conformation important for regulation of receptor signaling.