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Beta‐arrestin‐1 inhibits calcium sensing receptor (CaR)‐mediated MAPK signaling
Author(s) -
Zhang Mingliang,
Breitwieser Gerda E.
Publication year - 2006
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.20.5.a971-a
Subject(s) - phosphorylation , microbiology and biotechnology , arrestin , mapk/erk pathway , g protein coupled receptor , signal transduction , hek 293 cells , chemistry , kinase , beta adrenergic receptor kinase , transactivation , receptor , biology , biochemistry , gene expression , gene
[beta]‐arrestins regulate G protein‐coupled receptor (GPCR) desensitization and/or act as scaffolds for assembly of downstream signaling complexes. CaR regulates cell proliferation, differentiation and/or apoptosis via activation of mitogen‐activated protein kinase (MAPK) cascades via a pathway which includes transactivation of EGF receptors. We used immunoprecipitation (IP), mutagenesis and siRNA approaches in HEK293 cells to determine whether interaction of CaR with [beta]‐arrestin‐1 alters CaR‐mediated MAPK signaling. CaR and [beta]‐arrestin‐1 could be co‐IP'd from transiently transfected cells. siRNA knockdown of [beta]‐arrestin‐1 increased CaR‐mediated phosphorylation of extracellular signal‐regulated kinases 1 and 2 (ERK1/2~P), while exogenous expression of [beta]‐arrestin‐1 inhibited CaR‐mediated ERK1/2~P. To determine whether [beta]‐arrestin‐1 phosphorylation at residue S412 contributed to the effects on CaR‐mediated ERK1/2~P, we generated mutants S412A (a non‐phosphorylatable form) and S412D (to mimic the phosphorylated state). Both S412 mutants inhibited CaR‐mediated ERK1/2~P, suggesting that inhibition of CaR‐mediated ERK1/2~P was independent of S412 phosphorylation state. Overall, these results suggest that [beta]‐arrestin‐1 interacts with CaR and inhibits CaR‐mediated MAPK signaling. Supported by NIH GM58578 and funds from the Weis Center for Research, Geisinger Clinic.

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