PMID- 8955213
OWN - NLM
STAT- MEDLINE
DCOM- 19970123
LR  - 20131121
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 157
IP  - 12
DP  - 1996 Dec 15
TI  - Phosphorylation by a G protein-coupled kinase inhibits signaling and promotes 
      internalization of the monocyte chemoattractant protein-1 receptor. Critical role 
      of carboxyl-tail serines/threonines in receptor function.
PG  - 5606-12
AB  - Monocyte chemoattractant protein-1 (MCP-1) is a member of the chemokine family of 
      chemotactic cytokines and signals via activation of a G protein-coupled 
      seven-transmembrane domain receptor to mediate chemotaxis. Monocyte activation is 
      limited by desensitization and internalization of the MCP-1R, but these 
      mechanisms are not well understood. In this study, we show that the type B MCP-1R 
      (MCP-1RB/CCR2B) is rapidly phosphorylated and internalized in response to 
      nanomolar concentrations of MCP-1. Co-expression of CCR2B in Xenopus oocytes with 
      beta-adrenergic receptor kinase 2 (beta ark2), but not beta ark1 or rhodopsin 
      kinase, specifically blocked receptor activation by MCP-1. Mutation of serine 
      (Ser) and threonine (Thr) residues in the terminal carboxyl-tail of the receptor, 
      which are potential targets of beta ark-mediated phosphorylation, prevented 
      inhibition of receptor activation by beta ark2 in microinjected oocytes. Finally, 
      a construct in which multiple Ser and Thr residues in the carboxyl-tail were 
      changed to alanine significantly prolonged the agonist-dependent intracellular 
      calcium flux and inhibited receptor internalization in transfected human 
      embryonic kidney (HEK)-293 cells. These studies demonstrate that phosphorylation 
      of Ser and Thr residues in the carboxyl-tail of CCR2B mediates receptor 
      desensitization and internalization and may serve to limit the chemotactic 
      response of leukocytes to MCP-1 and related chemokines.
FAU - Franci, C
AU  - Franci C
AD  - Gladstone Institute of Cardiovascular Disease, University of California, San 
      Francisco 94143, USA.
FAU - Gosling, J
AU  - Gosling J
FAU - Tsou, C L
AU  - Tsou CL
FAU - Coughlin, S R
AU  - Coughlin SR
FAU - Charo, I F
AU  - Charo IF
LA  - eng
GR  - HL44907/HL/NHLBI NIH HHS/United States
GR  - HL52773/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (CCR2 protein, human)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (Receptors, Cytokine)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.15 (beta-Adrenergic Receptor Kinases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - Amino Acid Sequence
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - GTP-Binding Proteins/*physiology
MH  - Humans
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Phosphorylation
MH  - Receptors, CCR2
MH  - *Receptors, Chemokine
MH  - Receptors, Cytokine/chemistry/*physiology
MH  - Recombinant Fusion Proteins
MH  - Serine/chemistry
MH  - Signal Transduction
MH  - Structure-Activity Relationship
MH  - Threonine/chemistry
MH  - Tumor Cells, Cultured
MH  - beta-Adrenergic Receptor Kinases
EDAT- 1996/12/15 00:00
MHDA- 1996/12/15 00:01
CRDT- 1996/12/15 00:00
PHST- 1996/12/15 00:00 [pubmed]
PHST- 1996/12/15 00:01 [medline]
PHST- 1996/12/15 00:00 [entrez]
PST - ppublish
SO  - J Immunol. 1996 Dec 15;157(12):5606-12.