title: PLCε1 regulates SDF-1α-induced lymphocyte adhesion and migration to sites of inflammation.
abstract: Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCε1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structure-function experiments to separate the dual-enzymatic function of PLCε1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCε1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCε1, suggesting that PLCε1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Marianne
authors.initials: M
authors.lastname: Strazza
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Inbar
authors.initials: I
authors.lastname: Azoulay-Alfaguter
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Michael
authors.initials: M
authors.lastname: Peled
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016.|The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
authors.affiliation: The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016; Adam.Mor@NYUMC.org.|Department of Pathology, New York University School of Medicine, New York, NY 10016.|Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016.
authors.forename: Adam
authors.initials: A
authors.lastname: Mor
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D054801:Phosphoinositide Phospholipase C / Q000235:genetics* / Q000276:immunology; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology; D000089804:Shelterin Complex; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000276:immunology; D020666:ras-GRF1 / Q000276:immunology
chemical_list: D054377:Chemokine CXCL12; D011946:Receptors, Antigen; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D020666:ras-GRF1; D018799:Intercellular Adhesion Molecule-1; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon
keywords: PLCε1; Rap1; SDF-1α; T cells; adhesion