Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses

Kimberly N. Kremer, Ian C. Clift, Alexander G. Miamen, Adebowale O. Bamidele, Nan Xin Qian, Troy D. Humphreys, Karen Elaine Hedin

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The CXCR4 chemokine receptor is a G protein-coupled receptor that signals in T lymphocytes by forming a heterodimer with the TCR. CXCR4 and TCR functions are consequently highly cross regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAPK and downstream AP-1-dependent cytokine transcription in response to stromal cell-derived factor-1 (SDF-1), the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate G protein-coupled receptor-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. In this study, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-b3 to activate the Ras-ERK pathway and increase intracellular calcium ion concentrations, whereas PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1-mediated migration via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors to distinctly regulate migration versus other signaling functions.

Original languageEnglish (US)
Pages (from-to)1440-1447
Number of pages8
JournalJournal of Immunology
Volume187
Issue number3
DOIs
StatePublished - Aug 1 2011

Fingerprint

Chemokine CXCL12
Type C Phospholipases
T-Lymphocytes
Chemokine Receptors
G-Protein-Coupled Receptors
Cell Movement
Cytokines
CXCR4 Receptors
MAP Kinase Signaling System
Transcription Factor AP-1
Endocytosis
Chemokines
GTP-Binding Proteins
Protein-Tyrosine Kinases
Isoenzymes
Ions
Ligands
Calcium

ASJC Scopus subject areas

  • Immunology

Cite this

Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses. / Kremer, Kimberly N.; Clift, Ian C.; Miamen, Alexander G.; Bamidele, Adebowale O.; Qian, Nan Xin; Humphreys, Troy D.; Hedin, Karen Elaine.

In: Journal of Immunology, Vol. 187, No. 3, 01.08.2011, p. 1440-1447.

Research output: Contribution to journalArticle

Kremer, Kimberly N. ; Clift, Ian C. ; Miamen, Alexander G. ; Bamidele, Adebowale O. ; Qian, Nan Xin ; Humphreys, Troy D. ; Hedin, Karen Elaine. / Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses. In: Journal of Immunology. 2011 ; Vol. 187, No. 3. pp. 1440-1447.
@article{4a99bf4df524403e94075a595f70e1e4,
title = "Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses",
abstract = "The CXCR4 chemokine receptor is a G protein-coupled receptor that signals in T lymphocytes by forming a heterodimer with the TCR. CXCR4 and TCR functions are consequently highly cross regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAPK and downstream AP-1-dependent cytokine transcription in response to stromal cell-derived factor-1 (SDF-1), the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate G protein-coupled receptor-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. In this study, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-b3 to activate the Ras-ERK pathway and increase intracellular calcium ion concentrations, whereas PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1-mediated migration via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors to distinctly regulate migration versus other signaling functions.",
author = "Kremer, {Kimberly N.} and Clift, {Ian C.} and Miamen, {Alexander G.} and Bamidele, {Adebowale O.} and Qian, {Nan Xin} and Humphreys, {Troy D.} and Hedin, {Karen Elaine}",
year = "2011",
month = "8",
day = "1",
doi = "10.4049/jimmunol.1100820",
language = "English (US)",
volume = "187",
pages = "1440--1447",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "3",

}

TY - JOUR

T1 - Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses

AU - Kremer, Kimberly N.

AU - Clift, Ian C.

AU - Miamen, Alexander G.

AU - Bamidele, Adebowale O.

AU - Qian, Nan Xin

AU - Humphreys, Troy D.

AU - Hedin, Karen Elaine

PY - 2011/8/1

Y1 - 2011/8/1

N2 - The CXCR4 chemokine receptor is a G protein-coupled receptor that signals in T lymphocytes by forming a heterodimer with the TCR. CXCR4 and TCR functions are consequently highly cross regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAPK and downstream AP-1-dependent cytokine transcription in response to stromal cell-derived factor-1 (SDF-1), the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate G protein-coupled receptor-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. In this study, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-b3 to activate the Ras-ERK pathway and increase intracellular calcium ion concentrations, whereas PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1-mediated migration via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors to distinctly regulate migration versus other signaling functions.

AB - The CXCR4 chemokine receptor is a G protein-coupled receptor that signals in T lymphocytes by forming a heterodimer with the TCR. CXCR4 and TCR functions are consequently highly cross regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAPK and downstream AP-1-dependent cytokine transcription in response to stromal cell-derived factor-1 (SDF-1), the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate G protein-coupled receptor-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. In this study, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-b3 to activate the Ras-ERK pathway and increase intracellular calcium ion concentrations, whereas PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1-mediated migration via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors to distinctly regulate migration versus other signaling functions.

UR - http://www.scopus.com/inward/record.url?scp=80051627970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051627970&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1100820

DO - 10.4049/jimmunol.1100820

M3 - Article

C2 - 21705626

AN - SCOPUS:80051627970

VL - 187

SP - 1440

EP - 1447

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -