CCR7/CCL21 Migration on Fibronectin is Mediated by Phospholipase Cgamma1 and ERK1/2 in Primary T Lymphocytes

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Oct 5

PMID 20889506

Citations 21

Authors

Laura A Shannon

Psachal A Calloway

T Paul Welch

Charlotte M Vines

Affiliations

Soon will be listed here.

Abstract

CCR7 binds to its cognate ligand, CCL21, to mediate the migration of circulating naive T lymphocytes to the lymph nodes. T lymphocytes can bind to fibronectin, a constituent of lymph nodes, via their β1 integrins, which is a primary mechanism of T lymphocyte migration; however, the signaling pathways involved are unclear. We report that rapid (within 2 min) and transient phosphorylation of ERK1/2 is required for T cell migration on fibronectin in response to CCL21. Conversely, prevention of ERK1/2 phosphorylation by inhibition of its kinase, MAPK/MEK, prevented T lymphocyte migration. Previous studies have suggested that phospholipase Cγ1 (PLCγ1) can mediate phosphorylation of ERK1/2, which is required for β1 integrin activation. Paradoxically, we found that inhibition of PLCγ1 phosphorylation by the general PLC inhibitor U73122 was associated with a delayed and reduced phosphorylation of ERK1/2 and reduced migration of T lymphocytes on fibronectin. To further characterize the relationship between ERK1/2 and PLCγ1, we reduced PLCγ1 levels by 85% using shRNA and observed a reduced phosphorylation of ERK1/2 and a significant loss of CCR7-mediated migration of T lymphocytes on fibronectin. In addition, we found that inhibition of ERK1/2 phosphorylation by U0126 resulted in a decreased phosphorylation of PLCγ1, suggesting a feedback loop between ERK1/2 and PLCγ1. Overall, these results suggest that the CCR7 signaling pathway leading to T lymphocyte migration on fibronectin is a β1 integrin-dependent pathway involving transient ERK1/2 phosphorylation, which is modulated by PLCγ1.

Citing Articles

C-C Chemokine Receptor 7 Promotes T-Cell Acute Lymphoblastic Leukemia Invasion of the Central Nervous System via β2-Integrins.

Cardona C, Rodriguez A, Torres V, Sanchez A, Torres A, Vazquez A Int J Mol Sci. 2024; 25(17).

PMID: 39273598 PMC: 11395280. DOI: 10.3390/ijms25179649.

Systemic Administration of Cowpea Mosaic Virus Demonstrates Broad Protection Against Metastatic Cancers.

Chung Y, Zhao Z, Jung E, Omole A, Wang H, Sutorus L Adv Sci (Weinh). 2024; 11(18):e2308237.

PMID: 38430536 PMC: 11095214. DOI: 10.1002/advs.202308237.

Connecting the Dots: The Cerebral Lymphatic System as a Bridge Between the Central Nervous System and Peripheral System in Health and Disease.

Zhao H, Sun M, Zhang Y, Kong W, Fan L, Wang K Aging Dis. 2023; 15(1):115-152.

PMID: 37307828 PMC: 10796102. DOI: 10.14336/AD.2023.0516.

A meta-analysis indicates that the regulation of cell motility is a non-intrinsic function of chemoattractant receptors that is governed independently of directional sensing.

Rodriguez-Fernandez J, Criado-Garcia O Front Immunol. 2022; 13:1001086.

PMID: 36341452 PMC: 9630654. DOI: 10.3389/fimmu.2022.1001086.

Development of a human antibody that exhibits antagonistic activity toward CC chemokine receptor 7.

Jang M, Ismail N, Yu Y Antib Ther. 2022; 5(3):192-201.

PMID: 35967907 PMC: 9372883. DOI: 10.1093/abt/tbac016.

References

Kranenburg O, Moolenaar W . Ras-MAP kinase signaling by lysophosphatidic acid and other G protein-coupled receptor agonists. Oncogene. 2001; 20(13):1540-6. DOI: 10.1038/sj.onc.1204187. View

Pierce K, Premont R, Lefkowitz R . Seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002; 3(9):639-50. DOI: 10.1038/nrm908. View

Mould A, Garratt A, Askari J, Akiyama S, Humphries M . Identification of a novel anti-integrin monoclonal antibody that recognises a ligand-induced binding site epitope on the beta 1 subunit. FEBS Lett. 1995; 363(1-2):118-22. DOI: 10.1016/0014-5793(95)00301-o. View

Liu E, Sinha S, Williams C, Cyrille M, Heller E, Snapper S . Targeted deletion of integrin-linked kinase reveals a role in T-cell chemotaxis and survival. Mol Cell Biol. 2005; 25(24):11145-55. PMC: 1316981. DOI: 10.1128/MCB.25.24.11145-11155.2005. View

Szekanecz Z, Humphries M, Ager A . Lymphocyte adhesion to high endothelium is mediated by two beta 1 integrin receptors for fibronectin, alpha 4 beta 1 and alpha 5 beta 1. J Cell Sci. 1992; 101 ( Pt 4):885-94. DOI: 10.1242/jcs.101.4.885. View

Pullikuth A, Catling A . Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: a perspective. Cell Signal. 2007; 19(8):1621-32. PMC: 2233890. DOI: 10.1016/j.cellsig.2007.04.012. View

Vossmeyer D, Hofmann W, Loster K, Reutter W, Danker K . Phospholipase Cgamma binds alpha1beta1 integrin and modulates alpha1beta1 integrin-specific adhesion. J Biol Chem. 2001; 277(7):4636-43. DOI: 10.1074/jbc.M105415200. View

Redondo-Munoz J, Terol M, Garcia-Marco J, Garcia-Pardo A . Matrix metalloproteinase-9 is up-regulated by CCL21/CCR7 interaction via extracellular signal-regulated kinase-1/2 signaling and is involved in CCL21-driven B-cell chronic lymphocytic leukemia cell invasion and migration. Blood. 2007; 111(1):383-6. DOI: 10.1182/blood-2007-08-107300. View

Bajenoff M, Glaichenhaus N, Germain R . Fibroblastic reticular cells guide T lymphocyte entry into and migration within the splenic T cell zone. J Immunol. 2008; 181(6):3947-54. PMC: 2596721. DOI: 10.4049/jimmunol.181.6.3947. View

10.

Rong R, Ahn J, Chen P, Suh P, Ye K . Phospholipase activity of phospholipase C-gamma1 is required for nerve growth factor-regulated MAP kinase signaling cascade in PC12 cells. J Biol Chem. 2003; 278(52):52497-503. DOI: 10.1074/jbc.M306744200. View

11.

Faull R, Ginsberg M . Inside-out signaling through integrins. J Am Soc Nephrol. 1996; 7(8):1091-7. DOI: 10.1681/ASN.V781091. View

12.

Kaldjian E, Gretz J, Anderson A, Shi Y, Shaw S . Spatial and molecular organization of lymph node T cell cortex: a labyrinthine cavity bounded by an epithelium-like monolayer of fibroblastic reticular cells anchored to basement membrane-like extracellular matrix. Int Immunol. 2001; 13(10):1243-53. DOI: 10.1093/intimm/13.10.1243. View

13.

Gutkind J . Regulation of mitogen-activated protein kinase signaling networks by G protein-coupled receptors. Sci STKE. 2001; 2000(40):re1. DOI: 10.1126/stke.2000.40.re1. View

14.

Szekeres C, Tang K, Trikha M, Honn K . Eicosanoid activation of extracellular signal-regulated kinase1/2 in human epidermoid carcinoma cells. J Biol Chem. 2000; 275(49):38831-41. DOI: 10.1074/jbc.M002673200. View

15.

Huang C, Lee C, Chen M, Yang W, Chen Y, Chang C . Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-kappaB-dependent pathways. J Cell Physiol. 2009; 221(1):204-12. DOI: 10.1002/jcp.21846. View

16.

Jones N, Peak J, Brader S, Eccles S, Katan M . PLCgamma1 is essential for early events in integrin signalling required for cell motility. J Cell Sci. 2005; 118(Pt 12):2695-706. DOI: 10.1242/jcs.02374. View

17.

Gerthoffer W . Migration of airway smooth muscle cells. Proc Am Thorac Soc. 2007; 5(1):97-105. PMC: 2645306. DOI: 10.1513/pats.200704-051VS. View

18.

Cheung R, Malik M, Ravyn V, Tomkowicz B, Ptasznik A, Collman R . An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages. J Leukoc Biol. 2009; 86(4):833-45. PMC: 2752020. DOI: 10.1189/jlb.0908551. View

19.

Yang J, Vassil A, Hait W . Activation of phospholipase C induces the expression of the multidrug resistance (MDR1) gene through the Raf-MAPK pathway. Mol Pharmacol. 2001; 60(4):674-80. View

20.

Roberts O, Holmes K, Muller J, Cross D, Cross M . ERK5 and the regulation of endothelial cell function. Biochem Soc Trans. 2009; 37(Pt 6):1254-9. DOI: 10.1042/BST0371254. View