PMID- 12920215
OWN - NLM
STAT- MEDLINE
DCOM- 20030922
LR  - 20091119
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 64
IP  - 3
DP  - 2003 Sep
TI  - Signaling pathways for monocyte chemoattractant protein 1-mediated extracellular 
      signal-regulated kinase activation.
PG  - 773-82
AB  - G protein-coupled receptors (GPCRs) initiate diverse down-stream signaling events 
      in response to ligand stimulation, as rapid activation of the extracellular 
      signal-regulated kinase ERK1 and ERK2. The chemokine monocyte chemoattractant 
      protein-1 (MCP-1) is the agonist for several chemokine receptors that belong to 
      the GPCR superfamily, CCR2 being the most important. Stimulation of 
      mitogen-activated protein kinases (MAPKs) by MCP-1 has been implicated in 
      integrin activation and chemotaxis, but the molecular pathways down-stream of the 
      receptors remain unclear. To dissect the cascade of events leading to MAPK 
      activation upon CCR2 receptor stimulation, several specific inhibitors and 
      mutants of signal transduction proteins were used in monocytic cells endogenously 
      expressing CCR2 and/or in human embryonic kidney-293 cells transfected with CCR2B 
      receptors and epitope-tagged ERK1. We show that ERK activation by MCP-1 involves 
      heterotrimeric Gi protein subunits, protein kinase C, phosphoinositide-3-kinase, 
      and Ras. On the other hand, the activity of cytosolic tyrosine kinases, epidermal 
      growth factor receptor transactivation, or variations in intracellular calcium 
      levels are not required for the mitogenic activation elicited by MCP-1. In 
      addition, we find that internalization of CCR2B itself is not necessary for 
      efficient MCP-1-induced activation of ERK, although a dynamin mutant partially 
      inhibits ERK stimulation. These results suggest that different parallel pathways 
      are being activated that lead to the full activation of the mitogen-activated 
      protein kinase cascade and that internalization of other signaling proteins but 
      not of the receptor is required for complete ERK activation.
FAU - Jimenez-Sainz, M Carmen
AU  - Jimenez-Sainz MC
AD  - Department of Anatomy and Cell Biology, Faculty of Medicine, University of 
      Bergen, N-5009 Bergen, Norway. anna.aragay@pki.uib.no
FAU - Fast, Beate
AU  - Fast B
FAU - Mayor, Federico Jr
AU  - Mayor F Jr
FAU - Aragay, Anna M
AU  - Aragay AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Chemokine CCL2)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Cell Line
MH  - Chemokine CCL2/*physiology
MH  - Enzyme Activation/drug effects/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/*metabolism
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Signal Transduction/drug effects/*physiology
EDAT- 2003/08/16 05:00
MHDA- 2003/09/23 05:00
CRDT- 2003/08/16 05:00
PHST- 2003/08/16 05:00 [pubmed]
PHST- 2003/09/23 05:00 [medline]
PHST- 2003/08/16 05:00 [entrez]
AID - 64/3/773 [pii]
AID - 10.1124/mol.64.3.773 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2003 Sep;64(3):773-82. doi: 10.1124/mol.64.3.773.