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2142.Full.Pdf E-Selectin-Dependent Signaling Via the Mitogen-Activated Protein Kinase Pathway in Vascular Endothelial Cells This information is current as Yenya Hu, Jeanne-Marie Kiely, Brian E. Szente, Anthony of September 26, 2021. Rosenzweig and Michael A. Gimbrone, Jr. J Immunol 2000; 165:2142-2148; ; doi: 10.4049/jimmunol.165.4.2142 http://www.jimmunol.org/content/165/4/2142 Downloaded from References This article cites 47 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/165/4/2142.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. E-Selectin-Dependent Signaling Via the Mitogen-Activated Protein Kinase Pathway in Vascular Endothelial Cells1 Yenya Hu,* Jeanne-Marie Kiely,* Brian E. Szente,* Anthony Rosenzweig,† and Michael A. Gimbrone, Jr.2* E-selectin, a cytokine-inducible adhesion molecule, supports rolling and stable arrest of leukocytes on activated vascular endo- thelium. Previous studies have suggested that this transmembrane protein can also transduce signals into the endothelial cell. We now demonstrate activation of the mitogen-activated protein kinase (MAPK) signaling cascade in cultured HUVEC in response to E-selectin-dependent leukocyte adhesion and Ab-mediated cross-linking of cell surface E-selectin. Adhesion of increasing numbers of HL60 cells to IL-1␤-activated HUVEC stimulated robust increases in MAPK activity that were abrogated by an E-selectin blocking Ab. Cross-linking of cell surface E-selectin with Abs, as a mimic of multivalent ligand engagement, strongly stimulated MAPK/extracellular signal-related kinase (ERK) kinase (MEK)-dependent MAPK activation and concomitant up- Downloaded from regulation of mRNA for c-fos, an immediate early response gene, whereas Ab cross-linking of HLA class I molecules (present at comparable density) failed to do so. Coimmunoprecipitation documented Ras, Raf-1 and, phospho-MEK complex formation. Unactivated HUVEC transduced with a full-length adenoviral E-selectin construct also exhibited cross-link-induced MAPK ac- tivation, macromolecular complex formation, and c-fos up-regulation, whereas HUVEC transduced with a cytoplasmic domain deletion mutant failed to respond. These observations indicate that E-selectin can transduce an activating stimulus via the MAPK cascade into the endothelial cell during leukocyte adhesion. The Journal of Immunology, 2000, 165: 2142–2148. http://www.jimmunol.org/ he selectin family of adhesion molecules, which includes may also play a role in mediating the stable arrest of leukocytes on E-selectin, L-selectin, and P-selectin (1), mediates inter- the luminal surface of inflamed microvascular endothelium in the T action of circulating leukocytes with vascular endothe- mouse. lium in various physiological and pathological settings (1). Unique In addition to their function in supporting the physical adhesion among the selectin family molecules, E-selectin typically is not of leukocytes to the luminal surface of the vascular endothelium, detected in unactivated endothelial cells, but is rapidly synthesized recent studies suggest that selectins may also be playing a role in in response to certain cytokines and other pro-inflammatory stim- signal transduction during leukocyte-endothelial interactions. For by guest on September 26, 2021 uli, thus making it a marker of the “activated” endothelial pheno- example, our laboratory has shown that leukocyte adhesion to cy- type (2). Along with other selectin family members, E-selectin tokine-activated HUVEC induces clustering of E-selectin mole- exhibits a complex mosaic structure consisting of a large extracel- cules in the vicinity of leukocyte-endothelial cell attachment sites lular portion comprised of an amino-terminal lectin domain, an (8). Leukocyte adhesion to cytokine-activated HUVEC, or the Ab epidermal growth factor domain, and multiple complement regu- induced cross-linking of cell surface E-selectin molecules, results latory repeats, followed by a transmembrane portion and a rela- in a transmembrane linkage of E-selectin to the endothelial cy- tively short (32 aa) cytoplasmic domain (3). P-selectin glycopro- toskeleton via its cytoplasmic domain (8). More recently, Yoshida 3 tein ligand-1 (PSGL-1) can function as a ligand for both E- and et al. (9) have demonstrated that phosphorylation on serine resi- P-selectins (4), but other ligands appear to exist for E-selectin as dues in the cytoplasmic domain of E-selectin is modulated in well (5). E-selectin can support the initial rolling of leukocytes on HUVEC during engagement of E-selectin by leukocytes, Ab cross- activated endothelium as demonstrated in various in vitro and in linking or PSGL-coated beads. Taken together, these data suggest vivo models (3, 6). Milstone et al. (7) have shown that E-selectin that E-selectin can transduce transmembrane signals via its cyto- plasmic domain into the endothelial cell. Lorenzon et al. (10) also *Vascular Research Division, Department of Pathology, Brigham and Women’s Hos- have shown that the ligation of either P-selectin or E-selectin with pital, and †Program in Cardiovascular Gene Therapy, Cardiovascular Research Cen- mAbs can induce a transient increase of intracellular ionized cal- ter, Massachusetts General Hospital-East, Boston, MA 02115 cium in endothelial cell, thus further indicating a signaling func- Received for publication January 18, 2000. Accepted for publication May 30, 2000. tion for these vascular selectins. Extensive studies of L-selectin- The costs of publication of this article were defrayed in part by the payment of page dependent signaling in leukocytes also have been undertaken. For charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. example, Ab ligation of L-selectin on the leukocyte surface gen- 1 This work was supported by grants from the National Institutes of Health (P01- erates various transmembrane signals (11, 12), including, in- HL36028 to M.A.G. and HL54202 and AI40970 to A.R.). A.R. is an Established creased intracellular ionized calcium and production of superoxide Investigator of the American Heart Association. ␤ (13), activation of 2 integrin-dependent adhesion (14), and acti- 2 Address correspondence and reprint requests to Dr. Michael A. Gimbrone, Jr., Vas- vation of mitogen-activated protein kinase (MAPK) (15) and c-Jun cular Research Division, Department of Pathology, Brigham and Women’s Hospital, 221 Longwood Avenue, LMRC-401, Boston, MA 02115. E-mail address: N-terminal kinase (JNK) (16) signaling pathways. [email protected] The MAPK cascade (also known as the extracellular signal- 3 Abbreviations used in this paper: PSGL-1, P-selectin glycoprotein ligand-1; MAPK, regulated protein kinase, ERK, pathway) was originally described mitogen-activated protein kinase; ERK, extracellular signal-regulated protein kinase; MEK, MAPK/ERK kinase; GAM, goat anti-murine; WT-E, E-selectin wild type; in cells responding to soluble agonists, such as growth factors and ⌬Cyto-E, E-selectin cytoplasmic deletion. cytokines (17–19). The MAPK cascade consists of a three-kinase Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 The Journal of Immunology 2143 module that includes a MAPK, which is activated by a MAPK/ mixed and centrifuged for 2 min, and the supernatant was analyzed on a ERK kinase (MEK), which in turn is activated by a MEK kinase SDS-PAGE gel. (MEKK). Among the MEKKs, best characterized are the Raf pro- Immunoprecipitation and in vitro kinase assay for MAPK tein isoforms (20). The MAPK pathway can mediate various cel- activity lular responses, including cell motility and shape change, commit- ment to cell cycle or programmed cell death, as well as the MAPK activity was quantified using a kit (p44/42 MAP kinase) from New regulation of multiple genes encoding biologically active products England Biolabs (Beverly, MA), which measures phospho-Elk-1, the phos- phorylated product of activated MAPK in a standardized in vitro kinase (21). Activation of MAPK in endothelial cells also has been dem- assay. After treatment, HUVEC were rinsed with ice-cold PBS and lysed onstrated after stimulation by biomechanical force (22) as well as with the kit lysis buffer (20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM cytokine and growth factors (23, 24). Recently, ligand binding by EDTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM ␤-glyc- ␮ integrins or their Ab-mediated cross-linking has been shown to erolphosphate, 1 mM Na3VO4, and 1 g/ml leupeptin) on ice for 5 min. Total cell lysates were sonicated and centrifuged at 14,000 rpm for 15 min; activate MAPK in fibroblasts and endothelial cells (25, 26), and a then supernatants were transferred to new tubes and pre-cleared with pro- similar phenomenon has been observed following Ab cross-linking of tein A/G for1hat4°C. Aliquots (200 ␮l) of these supernatants were the Ig-type adhesion molecule, ICAM-1, in cultured HUVEC (27). incubated overnight at 4°C with the p44/42 MAPK mAb, which specifi- In this study, we have examined the ability of E-selectin-depen- cally recognizes and extracts the phosphorylated (“activated”) species of dent leukocyte adhesion or cross-linking of cell surface E-selectin MAPK.
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