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Membrane for Actin Bundle Formation P38 MAPK Signalosome at The Platelet-Activating Factor-Induced Clathrin-Mediated Endocytosis Requires β -Arrestin-1 Recruitment and Activation of the p38 MAPK Signalosome at the Plasma This information is current as Membrane for Actin Bundle Formation of September 24, 2021. Nathan J. D. McLaughlin, Anirban Banerjee, Marguerite R. Kelher, Fabia Gamboni-Robertson, Christine Hamiel, Forest R. Sheppard, Ernest E. Moore and Christopher C. Silliman J Immunol 2006; 176:7039-7050; ; Downloaded from doi: 10.4049/jimmunol.176.11.7039 http://www.jimmunol.org/content/176/11/7039 http://www.jimmunol.org/ References This article cites 49 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/176/11/7039.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Platelet-Activating Factor-Induced Clathrin-Mediated Endocytosis Requires ␤-Arrestin-1 Recruitment and Activation of the p38 MAPK Signalosome at the Plasma Membrane for Actin Bundle Formation1 Nathan J. D. McLaughlin,* Anirban Banerjee,† Marguerite R. Kelher,† Fabia Gamboni-Robertson,† Christine Hamiel,† Forest R. Sheppard,†‡ Ernest E. Moore,†‡ and Christopher C. Silliman2*†§ Clathrin-mediated endocytosis (CME) is a common pathway used by G protein-linked receptors to transduce extracellular signals. We hypothesize that platelet-activating factor (PAF) receptor (PAFR) ligation requires CME and causes engagement of ␤-arres- Downloaded from tin-1 and recruitment of a p38 MAPK signalosome that elicits distinct actin rearrangement at the receptor before endosomal scission. Polymorphonuclear neutrophils were stimulated with buffer or 2 ␮M PAF (1 min), and whole cell lysates or subcellular fractions were immunoprecipitated or slides prepared for colocalization and fluorescent resonance energy transfer analysis. In select experiments, ␤-arrestin-1 or dynamin-2 were neutralized by intracellular introduction of specific Abs. PAFR ligation caused 1) coprecipitation of the PAFR and clathrin with ␤-arrestin-1, 2) fluorescent resonance energy transfer-positive interactions among the PAFR, ␤-arrestin-1, and clathrin, 3) recruitment and activation of the apoptosis signal-regulating kinase-1/MAPK http://www.jimmunol.org/ kinase-3/p38 MAPK (ASK1/MKK3/p38 MAPK) signalosome, 4) cell polarization, and 5) distinct actin bundle formation at the PAFR. Neutralization of ␤-arrestin-1 inhibited all of these cellular events, including PAFR internalization; conversely, dynamin-2 inhibition only affected receptor internalization. Selective p38 MAPK inhibition globally abrogated actin rearrangement; however, inhibition of MAPK-activated protein kinase-2 and its downstream kinase leukocyte-specific protein-1 inhibited only actin bundle formation and PAFR internalization. In addition, ASK1/MKK3/p38 MAPK signalosome assembly appears to occur in a novel manner such that the ASK1/p38 MAPK heterodimer is recruited to a ␤-arrestin-1 bound MKK3. In polymorphonuclear neu- trophils, leukocyte-specific protein-1 may play a role similar to fascin for actin bundle formation. We conclude that PAF signaling requires CME, ␤-arrestin-1 recruitment of a p38 MAPK signalosome, and specific actin bundle formation at the PAFR for by guest on September 24, 2021 transduction before endosomal scission. The Journal of Immunology, 2006, 176: 7039–7050. he G protein-coupled receptors are ubiquitous, and bind- subunits (␣ and ␤␥) (5). These subunits cause the release of cal- ing of the ligand may cause receptor internalization via cium stores and the activation of small GTPases and MAPK sig- T clathrin-mediated endocytosis (CME),3 which activates naling cascades (5). Within seconds, these signals can be termi- specific signaling pathways (1). Classically, CME consists of three nated by members of the arrestin family by their binding to the steps: receptor desensitization, sequestration of receptors to clath- phosphorylated C terminus (cytosolic) region of the receptor and rin-coated pits, and receptor internalization (2, 3). However, there uncoupling it from the associated heteromeric G proteins (2). In is increasing evidence for discrete signal transduction at the site of addition, arrestins may have a role in receptor internalization and the receptor for each step in CME (2, 4). The initial signal is nonreceptor tyrosine kinase activation (4, 6). transduced via coupling of the receptor to heteromeric G protein Cell motility is essential for host defense, especially for leuko- cyte recruitment to the site of injury. Polymorphonuclear neutro- *Department of Pediatrics and †Department of Surgery, University of Colorado phils (PMNs) play a key role in host defense, and exert their mi- School of Medicine, Denver, CO 80262; ‡Department of Surgery, Denver Health crobicidal function in the tissues. The orderly process of migration Medical Center, Denver, CO 80204; and §Bonfils Blood Center, Denver, CO 80230 from the vasculature to the tissue initiates PMN priming, which Received for publication August 16, 2005. Accepted for publication March 13, 2006. can be facilitated by a number of proinflammatory protein and The costs of publication of this article were defrayed in part by the payment of page lipid mediators, including IL-8, leukotriene B4, and platelet-acti- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. vating factor (PAF) (7–10). PMN priming is characterized by 1 distinct physiological changes, including increased actin polymer- This work was supported by Bonfils Blood Center, Grant HL-59355-06 from the ␤ National Heart, Lung, and Blood Institute and Grant GM-49222 from the National ization resulting in shape change, firm 2 integrin-mediated ad- Institute of General Medical Sciences. herence to the vascular endothelium, and augmentation of the mi- 2 Address correspondence and reprint requests to Dr. Christopher C. Silliman, crobicidal response, both oxidative and nonoxidative, to a Bonfils Blood Center, 717 Yosemite Street, Denver, CO 80230. E-mail address: [email protected] subsequent stimulus. In addition, PMN priming agents are etio- logic in two event models of PMN-mediated acute lung injury, 3 Abbreviations used in this paper: CME, clathrin-mediated endocytosis; PMN, poly- morphonuclear neutrophil; PAF, platelet-activating factor; PAFR, PAF receptor; sepsis, and multiple organ failure (11, 12). ASK1, apoptosis signal-regulating kinase-1; MKK, MAPK kinase-3; MAPKAPK-2, Ligation of the PAF receptor (PAFR) recruits members of the MAPK-activated protein kinase-2; LSP-1, leukocyte-specific protein-1; FRET, fluo- ␤ rescent resonance energy transfer; PAK, p21-activated kinase; ARP, actin-related arrestin family ( -arrestin-1), which desensitizes the receptor, protein; TAK, TGF-␤ activated-kinase-1. operationally defined as the inability of repeated exposures to a Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 7040 PAF CME REQUIRES ␤-ARRESTIN IN p38-INDUCED ACTIN BUNDLES stimulus to cause multiple signaling events, e.g., the release of strument filter control. Images were acquired using Intelligent Imaging stored Ca2ϩ (13). However, the role of these arresting proteins to Innovations SlideBook software. All images compared within a single fig- ␮ facilitate signaling remains undefined. We hypothesize that PAF ure were acquired as Z-stacks in 0.2- m intervals, and the planes are as described in the figures. All Z-stack images were deconvolved by applying causes CME of its receptor and before endosomal scission elicits constrained iterative deconvolution and Gaussian noise smoothing from ␤-arrestin-1-mediated recruitment and activation of the p38 system specific point spread functions (17). Following deconvolution, im- MAPK signalosome and discrete actin reorganization at the PAFR, ages were cropped to represent the middle most planes (center Ϯ 10 all required for CME and distinct from actin that participates in planes) and the proteins in question masked to represent zero fluorescence in IgG negative controls. Cell polarization was assessed using Nomarski cell polarization and chemotaxis. differential interference contrast microscopy (Nomarski images), and for these images, microscopy planes were taken through the pseudopodia as Materials and Methods described in the figures (18). Materials Fluorescent resonance energy transfer (FRET) microscopy Unless otherwise indicated, all chemicals were purchased from Sigma- Aldrich. All reagents were endotoxin-free, and all solutions were made FRET determinations were obtained by direct acceptor photobleaching from sterile water (Pharmacopeia). Acrylamide, N,NЈ-methylene-bis-acryl- FRET as previously described (19). Within this
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