PMID- 10574913
OWN - NLM
STAT- MEDLINE
DCOM- 20000203
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 49
DP  - 1999 Dec 3
TI  - Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by
      extracellular signal-regulated kinases.
PG  - 34531-4
AB  - G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and
      beta-arrestin binding uncouple G protein-coupled receptors (GPCRs) from their
      respective G proteins and initiates the process of receptor internalization. In
      the case of the beta(2)-adrenergic receptor and lysophosphatidic acid receptor,
      these processes can lead to ERK activation. Here we identify a novel mechanism
      whereby the activity of GRK2 is regulated by feedback inhibition. GRK2 is
      demonstrated to be a phosphoprotein in cells. Mass spectrometry and mutational
      analysis localize the site of phosphorylation on GRK2 to a carboxyl-terminal
      serine residue (Ser(670)). Phosphorylation at Ser(670) impairs the ability of
      GRK2 to phosphorylate both soluble and membrane-incorporated receptor substrates 
      and dramatically attenuates Gbetagamma-mediated activation of this enzyme.
      Ser(670) is located in a peptide sequence that conforms to an ERK consensus
      phosphorylation sequence, and in vitro, in the presence of heparin, ERK1
      phosphorylates GRK2. Inhibition of ERK activity in HEK293 cells potentiates GRK2 
      activity, whereas, conversely, ERK activation inhibits GRK2 activity. The
      discovery that ERK phosphorylates and inactivates GRK2 suggests that ERK
      participates in a feedback regulatory loop. By negatively regulating GRK-mediated
      receptor phosphorylation, beta-arrestin-mediated processes such as Src
      recruitment and clathrin-mediated internalization, which are required for
      GPCR-mediated ERK activation, are inhibited, thus dampening further ERK
      activation.
FAU - Pitcher, J A
AU  - Pitcher JA
AD  - Howard Hughes Medical Institute, Department of Medicine, Duke University Medical 
      Center, Durham, North Carolina 27710, USA.
FAU - Tesmer, J J
AU  - Tesmer JJ
FAU - Freeman, J L
AU  - Freeman JL
FAU - Capel, W D
AU  - Capel WD
FAU - Stone, W C
AU  - Stone WC
FAU - Lefkowitz, R J
AU  - Lefkowitz RJ
LA  - eng
GR  - HL16037/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Phosphoproteins)
RN  - 452VLY9402 (Serine)
RN  - 9009-81-8 (Rhodopsin)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.15 (beta-Adrenergic Receptor Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP3K1 protein, human)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - Cell Line
MH  - Chromatography
MH  - Cyclic AMP-Dependent Protein Kinases/*antagonists &
      inhibitors/chemistry/genetics/metabolism/*physiology
MH  - Dose-Response Relationship, Drug
MH  - GTP-Binding Proteins/metabolism
MH  - *Gene Expression Regulation, Enzymologic
MH  - Humans
MH  - *MAP Kinase Kinase Kinase 1
MH  - MAP Kinase Kinase Kinases/metabolism
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinases/pharmacokinetics/*physiology
MH  - Mutagenesis, Insertional
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Precipitin Tests
MH  - *Protein-Serine-Threonine Kinases
MH  - Rhodopsin/metabolism
MH  - Serine/metabolism
MH  - Signal Transduction
MH  - beta-Adrenergic Receptor Kinases
EDAT- 1999/11/27 00:00
MHDA- 1999/11/27 00:01
CRDT- 1999/11/27 00:00
PHST- 1999/11/27 00:00 [pubmed]
PHST- 1999/11/27 00:01 [medline]
PHST- 1999/11/27 00:00 [entrez]
AID - 10.1074/jbc.274.49.34531 [doi]
AID - S0021-9258(19)53356-7 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Dec 3;274(49):34531-4. doi: 10.1074/jbc.274.49.34531.