PMID- 10521508
OWN - NLM
STAT- MEDLINE
DCOM- 19991123
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 43
DP  - 1999 Oct 22
TI  - Trafficking of the HIV coreceptor CXCR4. Role of arrestins and identification of 
      residues in the c-terminal tail that mediate receptor internalization.
PG  - 31076-86
AB  - The G protein-coupled chemokine receptor CXCR4 serves as the primary coreceptor
      for entry of T-cell tropic human immunodeficiency virus. CXCR4 undergoes tonic
      internalization as well as internalization in response to stimulation with
      phorbol esters and ligand (SDF-1alpha). We investigated the trafficking of this
      receptor, and we attempted to define the residues of CXCR4 that were critical for
      receptor internalization. In both COS-1 and HEK-293 cells transiently
      overexpressing CXCR4, SDF-1alpha and phorbol esters (PMA) promoted rapid
      internalization of cell surface receptors as assessed by both enzyme-linked
      immunosorbent assay and immunofluorescence analysis. Expression of GRK2 and/or
      arrestins promoted modest additional CXCR4 internalization in response to both
      PMA and SDF. Both PMA- and SDF-mediated CXCR4 internalization was inhibited by
      coexpression of dominant negative mutants of dynamin-1 and arrestin-3. Arrestin
      was also recruited to the plasma membrane and appeared to colocalize with
      internalized receptors in response to SDF but not PMA. We then evaluated the
      ability of CXCR4 receptors containing mutations of serines and threonines, as
      well as a dileucine motif, within the C-terminal tail to be internalized and
      phosphorylated in response to either PMA or SDF-1alpha. This analysis showed that
      multiple residues within the CXCR4 C-terminal tail appear to mediate both PMA-
      and SDF-1alpha-mediated receptor internalization. The ability of coexpressed GRK2
      and arrestins to promote internalization of the CXCR4 mutants revealed distinct
      differences between respective mutants and suggested that the integrity of the
      dileucine motif (Ile-328 and Leu-329) and serines 324, 325, 338, and 339 are
      critical for receptor internalization.
FAU - Orsini, M J
AU  - Orsini MJ
AD  - Department of Microbiology, Kimmel Cancer Institute, Thomas Jefferson University,
      Philadelphia, Pennsylvania 19107, USA.
FAU - Parent, J L
AU  - Parent JL
FAU - Mundell, S J
AU  - Mundell SJ
FAU - Marchese, A
AU  - Marchese A
FAU - Benovic, J L
AU  - Benovic JL
LA  - eng
GR  - 5-T32-DK07705/DK/NIDDK NIH HHS/United States
GR  - GM47419/GM/NIGMS 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 (Arrestins)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (Chemokine CCL5)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Chemokines, CXC)
RN  - 0 (Receptors, CCR5)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Recombinant Proteins)
RN  - 0 (arrestin3)
RN  - 452VLY9402 (Serine)
RN  - EC 3.5.1.50 (Dynamin I)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.5.5 (Dynamins)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
SB  - X
EIN - J Biol Chem 2000 Aug 18;275(33):25876. Marchese, Adriano [added]
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Arrestins/genetics/*metabolism
MH  - COS Cells
MH  - Cell Line
MH  - Cell Membrane/drug effects/physiology
MH  - Chemokine CCL5/pharmacology
MH  - Chemokine CXCL12
MH  - Chemokines, CXC/pharmacology
MH  - Dynamin I
MH  - Dynamins
MH  - Endocytosis/drug effects
MH  - GTP Phosphohydrolases/genetics/*metabolism
MH  - HIV/*physiology
MH  - Humans
MH  - Kinetics
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Receptors, CCR5/metabolism
MH  - Receptors, CXCR4/*chemistry/genetics/*metabolism
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Sequence Alignment
MH  - Serine
MH  - Stromal Cells/physiology
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Transfection
EDAT- 1999/10/16 00:00
MHDA- 1999/10/16 00:01
CRDT- 1999/10/16 00:00
PHST- 1999/10/16 00:00 [pubmed]
PHST- 1999/10/16 00:01 [medline]
PHST- 1999/10/16 00:00 [entrez]
AID - 10.1074/jbc.274.43.31076 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Oct 22;274(43):31076-86. doi: 10.1074/jbc.274.43.31076.