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Determination of bradykinin B2 receptor in vivo phosphorylation sites and their role in receptor function

Blaukat, Andree (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Pizard, Anne (författare)
Breit, Andreas (författare)
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Wernstedt, Christer (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
Alhenc-Gelas, François (författare)
Müller-Esterl, Werner (författare)
Dikic, Ivan (författare)
Uppsala universitet,Ludwiginstitutet för cancerforskning
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 (creator_code:org_t)
2001
2001
Engelska.
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 276:44, s. 40431-40440
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • Reversible phosphorylation plays important roles in G protein-coupled receptor signaling, desensitization, and endocytosis, yet the precise location and role of in vivo phosphorylation sites is unknown for most receptors. Using metabolic 32P labeling and phosphopeptide sequencing we provide a complete phosphorylation map of the human bradykinin B2 receptor in its native cellular environment. We identified three serine residues, Ser(339), Ser(346), and Ser(348), at the C-terminal tail as principal phosphorylation sites. Constitutive phosphorylation occurs at Ser(348), while ligand-induced phosphorylation is found at Ser(339) and Ser(346)/Ser(348) that could be executed by several G protein-coupled receptor kinases. In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. This was further supported by the specifically reduced Ser(346)/Ser(348) phosphorylation observed upon stimulation with a nondesensitizing B2 receptor agonist. The differential usage of clustered phosphoacceptor sites points to distinct roles of multiple kinases in controlling G protein-coupled receptor function.

Nyckelord

Amino Acid Sequence
Cell Line
Humans
Kinetics
Molecular Sequence Data
Mutagenesis; Site-Directed
Peptide Mapping
Phosphorylation
Receptor; Bradykinin B2
Receptors; Bradykinin/chemistry/genetics/*metabolism/physiology
Research Support; Non-U.S. Gov't
Serine/*metabolism

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