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Differential Regulation of Chemoattractant-Stimulated β2, β3, and β7 Integrin Activity This information is current as Chanchal Sadhu, Boris Masinovsky and Donald E. Staunton of September 26, 2021. J Immunol 1998; 160:5622-5628; ; http://www.jimmunol.org/content/160/11/5622 Downloaded from References This article cites 24 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/160/11/5622.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 26, 2021 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. b b Differential Regulation of Chemoattractant-Stimulated 2, 3, b and 7 Integrin Activity Chanchal Sadhu,1 Boris Masinovsky, and Donald E. Staunton Leukocyte adhesion to endothelium and extravasation are dynamic processes that require activation of integrins. Chemoattrac- tants such as IL-8 and FMLP are potent activators of leukocyte integrins. To compare the chemoattractant-stimulated activation a b a b a b of three integrins, 4 7, L 2, and V 3, in the same cellular context, we expressed an IL-8 receptor (IL-8RA) and FMLP receptor a b a b (FPR) in the lymphoid cell line JY. Chemoattractants induced a rapid increase in L 2- and V 3-dependent JY adhesion within a b 5 min, and it was sustained for 30 min. In contrast, stimulation of 4 7-dependent adhesion was transient, returning to basal levels by 30 min. The activation profiles of the integrins were similar regardless of whether IL-8 or FMLP was used for induction. We a b also demonstrate that 4 7-dependent adhesion was uniquely responsive to the F actin-disrupting agent cytochalasin D and the a b a b Downloaded from protein kinase C (PKC) inhibitor chelerythrin. While V 3- and L 2-mediated cell adhesion was significantly reduced by a b a b cytochalasin D, 4 7-mediated adhesion was enhanced. Chelerythrin inhibited both the IL-8 and PMA activation of L 2 and a b a b V 3. In contrast, inducible 4 7 activity was unaffected, and basal activity was increased. These findings demonstrate that the a b a b a b mechanism of 4 7 regulation by chemoattractants is different from that of L 2 and V 3 and that it appears to involve distinct cytoskeletal and PKC dependencies. In addition, PKC activity may be a positive or negative regulator of integrin-dependent adhesion. The Journal of Immunology, 1998, 160: 5622–5628. http://www.jimmunol.org/ xtravasation of circulating leukocytes through the endo- that protein kinase C (PKC2) and phosphatidyl inositol-3 kinase thelium into tissues is a multistep process involving pri- contribute to the signals leading to integrin activation (10). Work E mary and secondary adhesion (1–4). Primary adhesion by Campbell et al. (11) and Weber et al. (8) suggests a complex involves an interaction with a rapid association and dissociation effect by chemoattractants on integrin activation and chemotaxis. rate that mediates initial contact and rolling of leukocytes on en- The T cell line Jurkat, expressing the receptors for IL-8, MIP-1a, a b a b dothelium under flow conditions. Selectins and the integrins 4 1 C5a, or FMLP, showed a strong but transient activation of 4 1- a b and 4 7 can mediate primary adhesion (1, 5). During secondary dependent adhesion in the presence of a high concentration of the adhesion, leukocytes adhere firmly to the endothelium and undergo appropriate agonist (11). However, suppression of chemotaxis was b a by guest on September 26, 2021 a change in cell shape. Binding of leukocyte 2 (CD18) and 4 observed at higher than optimum agonist concentrations, indicat- integrins to endothelial cell ICAMs and VCAM-1 can mediate ing distinct regulation of adhesion and chemotaxis. Stimulation of secondary adhesion (1, 3). human eosinophils with RANTES, MCP-3, or C5a produced a a b Firm adhesion of leukocytes to the endothelium is dependent on rapid and transient activation of 4 1 but prolonged activation of a b b signaling that leads to integrin activation, which is manifested in M 2 (8). These results suggest a differential regulation of the 1 b increased avidity for ligands. Leukocyte integrins can be activated and 2 integrins. via different receptor types. For example, engagement of T cell Here, we report different signaling and cytoskeletal require- surface molecules such as TCR and L-selectin has been shown to ments for chemoattractant-stimulated activation of three integrins a b activate binding of the leukointegrin L 2 (CD11a/CD18, LFA-1) in the background of one cell type. We have generated lymphoid to ICAM-1 (6, 7). In addition, soluble mediators such as chemoat- cell lines to address the mechanism of integrin activation subse- tractants including chemokines have been reported to induce in- quent to stimulation by agonists of G protein-coupled receptors. creased integrin-dependent leukocyte adhesion. Classical chemoat- Thus, we have studied IL-8- and FMLP-mediated activation of a b a b a b tractants such as FMLP and C5a have been shown to activate 4 7, v 3, and L 2 in a B lymphoid cell line, JY, expressing CD18 integrins on eosinophils (8). Among the different chemo- IL-8 or FMLP receptors. Our results demonstrate a distinct regu- a b a b a b kines, IL-8 can activate integrins on neutrophils and regulate trans- lation of 4 7 integrin activity relative to that of L 2 and v 3 endothelial migration of neutrophils (9). integrins. Chemoattractants activate integrins subsequent to binding their heterotrimeric G protein-coupled receptors. However, little is Materials and Methods known of the exact downstream signaling pathway or the effects of Antibodies these inducers on individual integrins. Emerging evidence suggest The FLAG epitope-specific mAb M1 was from Eastman Kodak (Roches- a ter, NY). Cells producing the L mAb, TS1/22, were from American Type b Culture Collection (ATCC), Rockville, MD, and the 1 mAb, 3S3, was a ICOS Corporation, Bothell, WA 98021 gift from Dr. John Wilkins, University of Manitoba (Winnipeg, Canada). b a Received for publication October 30, 1997. Accepted for publication February The 2 mAb, 22F12C, and the 4 mAb, 72A1H, were generated at ICOS. b b 3, 1998. Fib 504.64, a rat anti-mouse 7 mAb (12) that also binds to human 7, was The costs of publication of this article were defrayed in part by the payment of page obtained from ATCC. All of the Abs were purified according to standard charges. This article must therefore be hereby marked advertisement in accordance procedures. with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Address correspondence and reprint requests to Dr. Chanchal Sadhu, ICOS Corp., 22021 20th Avenue SE, Bothell, WA 98021. 2 Abbreviations used in this paper: PKC, protein kinase C; FPR, FMLP receptor. Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 5623 Generation of human lymphoid cell lines expressing IL-8 or family. Based on their pertussis toxin sensitivity, it is believed that FMLP receptor both of these receptors transduce a signal through the Gi class of The human IL-8RA (IL-8 receptor subtype A) (13) sequence was amplified G proteins (15, 16). These receptors were tagged with the FLAG from genomic DNA. The FMLP receptor (FPR) cDNA was a gift from Dr. epitope at their N termini and were expressed in the human B a b a b Richard Ye (The Scripps Research Institute, La Jolla, CA). HindIII and lymphoid cell line JY. JY cells express the integrins L 2, v 3, XbaI restriction endonuclease sites were added by PCR to the 59 and 39 a b and 4 7 (Fig. 1), all of which may be stimulated by PMA (data ends of the IL-8RA and the FPR cDNA clones. For IL-8RA, the following 9 9 not shown). The untransfected cells did not respond to the che- oligonucleotide primers were used: 5 (HindIII), 5 ATGCAAGCTT a b a b a b TCAAAT ATTACAGATCCA 39; and 39 (XbaI), 59ATGCTCTAGATTT moattractants, as there was no increased L 2-, V 3-, or 4 7- TCAGAGGTTGGAAGAG AC 39. Sequences of the oligonucleotide prim- dependent binding observed in the presence of either FMLP or ers used for the FPR cDNA are: 59 (HindIII), 59ATGCAAGCTTGAG IL-8 (data not presented). After transfection and G418 selection, ACAAATTCCTCTCTC 39; and 39 (XbaI), 59ATGCTCTAG ATCACTT cells were sorted using a mAb that binds to the FLAG epitope. TGCCTGTAACGCCAC 39. The PCR-amplified products were verified by DNA sequencing. The mammalian expression vector, pcDNA3 (Invitro- Following two rounds of sorting, cell lines expressing high levels gen, San Diego, CA) was modified by inserting the bovine prolactin signal of FPR (JY-fp) and IL-8RA (JY-8) were established (Fig. 1). Cell sequence and the FLAG epitope (Eastman Kodak) 3 prime to the CMV surface expression of both the IL-8 and FMLP receptors remained promoter.
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  • Syndecan-1 Couples the Insulin-Like Growth Factor-1 Receptor to Inside-Out Integrin Activation

    Syndecan-1 Couples the Insulin-Like Growth Factor-1 Receptor to Inside-Out Integrin Activation

    3796 Research Article Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation DeannaLee M. Beauvais and Alan C. Rapraeger* Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA *Author for correspondence ([email protected]) Accepted 28 July 2010 Journal of Cell Science 123, 3796-3807 © 2010. Published by The Company of Biologists Ltd doi:10.1242/jcs.067645 Summary Syndecan-1 (Sdc1) engages and activates the avb3 (and/or avb5) integrin when clustered in human carcinoma and endothelial cells. Although the engagement is extracellular, the activation mechanism is cytoplasmic. This talin-dependent, inside-out signaling pathway is activated downstream of the insulin-like growth factor-1 receptor (IGF1R), whose kinase activity is triggered by Sdc1 clustering. In vitro binding assays using purified receptors suggest that association of the Sdc1 ectodomain with the integrin provides a ‘docking face’ for IGF1R. IGF1R docking and activation of the associated integrin is blocked by synstatin (SSTN92–119), a peptide derived from the integrin engagement site in Sdc1. IGF1R colocalizes with avb3 integrin and Sdc1 in focal contacts, but fails to associate with or activate the integrin in cells either lacking Sdc1 or expressing Sdc1D67–121, a mutant that is unable to form the Sdc1–integrin–IGF1R ternary complex. Integrin activation is also blocked by IGF1R inhibitors or by silencing IGF1R or talin expression with small- interfering RNAs (siRNAs). In both cases, expression of the constitutively active talin F23 head domain rescues integrin activation. We recently reported that SSTN92–119 blocks angiogenesis and impairs tumor growth in mice, therefore this Sdc1-mediated integrin regulatory mechanism might be a crucial regulator of disease processes known to rely on these integrins, including tumor cell metastasis and tumor-induced angiogenesis.