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And Phospho-Proteomics Reveal Lck As a Major Signaling Hub of CD147 in T Cells

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And Phospho-Proteomics Reveal Lck As a Major Signaling Hub of CD147 in T Cells Dynamic Interaction- and Phospho-Proteomics Reveal Lck as a Major Signaling Hub of CD147 in T Cells This information is current as Verena Supper, Ingrid Hartl, Cyril Boulègue, Anna of September 28, 2021. Ohradanova-Repic and Hannes Stockinger J Immunol 2017; 198:2468-2478; Prepublished online 1 February 2017; doi: 10.4049/jimmunol.1600355 http://www.jimmunol.org/content/198/6/2468 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/02/01/jimmunol.160035 Material 5.DCSupplemental http://www.jimmunol.org/ References This article cites 92 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/198/6/2468.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dynamic Interaction- and Phospho-Proteomics Reveal Lck as a Major Signaling Hub of CD147 in T Cells Verena Supper,* Ingrid Hartl,* Cyril Boule`gue,† Anna Ohradanova-Repic,* and Hannes Stockinger* Numerous publications have addressed CD147 as a tumor marker and regulator of cytoskeleton, cell growth, stress response, or im- mune cell function; however, the molecular functionality of CD147 remains incompletely understood. Using affinity purification, mass spectrometry, and phosphopeptide enrichment of isotope-labeled peptides, we examined the dynamic of the CD147 microenvironment and the CD147-dependent phosphoproteome in the Jurkat T cell line upon treatment with T cell stimulating agents. We identified novel dynamic interaction partners of CD147 such as CD45, CD47, GNAI2, Lck, RAP1B, and VAT1 and, furthermore, found 76 CD147- dependent phosphorylation sites on 57 proteins. Using the STRING protein network database, a network between the CD147 micro- environment and the CD147-dependent phosphoproteins was generated and led to the identification of key signaling hubs around the G Downloaded from proteins RAP1B and GNB1, the kinases PKCb, PAK2, Lck, and CDK1, and the chaperone HSPA5. Gene ontology biological process term analysis revealed that wound healing–, cytoskeleton-, immune system–, stress response–, phosphorylation- and protein mod- ification–, defense response to virus–, and TNF production–associated terms are enriched within the microenvironment and the phosphoproteins of CD147. With the generated signaling network and gene ontology biological process term grouping, we identify potential signaling routes of CD147 affecting T cell growth and function. The Journal of Immunology, 2017, 198: 2468–2478. http://www.jimmunol.org/ D147 is a ubiquitously expressed type 1 transmembrane the amino acid transporter CD98 H chain (CD98) (54, 55), has glycoprotein belonging to the Ig superfamily. It is therefore been shown to affect cell growth and survival by modulating in- C not surprising that it is involved in a plethora of cell tracellular lactate or amino acid concentrations and stimulating functions such as cell proliferation (1–15), cell death (11, 12, 16– PI3K/PKB (3, 55). The activation of PI3K/PKB and subsequent 22), stress response (17, 23), chemosensitivity (10, 17, 21, 24, 25), activation of the MAPK pathway upon engagement of CD147 with chemotaxis (9, 26–34), migration (1, 2, 10–13, 18, 33, 35–41), cyclophilins has also been observed to support cell proliferation (56, adhesion (1, 6, 14, 33, 35, 42–45), and metabolism (3, 5, 16). 57), stress protection (23–25), and chemotactic processes (9, 26–32, Concomitantly, the effect of CD147 on these cellular functions has 43, 58). Moreover, activation of PI3K (59) and ERK (36) were found implications in the regulation of T cell activity (1, 4, 6–9, 14, 15, to be prerequisites for the CD147/b1-integrin–dependent modulation by guest on September 28, 2021 34, 46–48), cancer (5, 13, 49–51), and metastasis (37–41, 52), and of FAK activation and the adhesive capacities of cells. Activation of makes CD147 an ideal disease marker and therapy target (49, 53). FAK and MAPKs and the cytoskeletal regulators vinculin and pax- In using CD147 as a therapy target, it is essential to understand illin were shown to be involved in subsequent CD147-dependent the possible signaling outcomes, and several attempts have been cytoskeletal changes in actin, microtubule, and vimentin fila- made to understand CD147-dependent molecular mechanisms. ments (60, 61). In addition to cytoskeletal processes, CD147 The interaction of CD147 with transporters, such as the mono- has also been observed to protect cells from apoptosis by carboxylate transporters 1 and 4 (MCT1 and MCT4) (3, 5, 16) or regulating caspase-3 (19, 20, 22), BIM (20, 22), Bcl-2 (20), *Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Cen- The online version of this article contains supplemental material. ter of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Abbreviations used in this article: ACIN1, apoptotic chromatin condensation inducer 1; 1090 Vienna, Austria; and †Microchemistry Core Facility, Max Planck Institute of AP-MS, affinity-purification mass spectrometry; ARHGEF2, Rho/Rac guanine nu- Biochemistry, 82152 Martinsried, Germany cleotide exchange factor 2; ATP1A1, Na+/K+ ATPase a-1 subunit; B2M, b-2-micro- ORCIDs: 0000-0003-2831-600X (V.S.); 0000-0002-8005-8522 (A.O.-R.); 0000- globulin; CD226, platelet and T cell activation antigen 1; CD43, sialophorin; CD45, 0001-6404-4430 (H.S.). protein tyrosine phosphatase receptor type C; CD47, integrin-associated signal trans- ducer CD47; CD98, amino acid transporter CD98 H chain; CDK1, cyclin-dependent Received for publication February 29, 2016. Accepted for publication January 6, kinase 1; CFL1, cofilin 1; DOCK2, dedicator of cytokinesis 2; GNAI2, G protein a 2017. inhibiting activity polypeptide 2; GNB1, G protein b polypeptide 1; GOBP, gene This work was supported by the GEN-AU-Program of the Austrian Federal Ministry ontology biological process; G protein, guanine nucleotide binding protein; HA, of Science and Research (FA644A0103), the Austrian Research Promotion Agency hemagglutinin; HACD147etc, HA-tagged RNAi-resistant CD147; HSPA5, heat (Mobility Stipendium 831947), the Seventh Framework Program (FP7/2007-2013) shock 70 kDa protein 5; Lck, lymphocyte-specific protein tyrosine kinase; MAP1A, under Grant Agreement NMP4-LA-2009-228827 NANOFOL and the European microtubule-associated protein 1A; MCT1, monocarboxylate transporter 1; MCT4, Union’s Horizon 2020 Research and Innovation Program under Grant Agreement monocarboxylate transporter 4; MYH10, myosin-10; NCOR1, nuclear receptor co- 683356. repressor 1; PAK2, p21-activated kinase 2; PKCb, protein kinase C b; PMCA4, plasma membrane calcium ATPase isoform 4; RAP1B, Ras family small GTP bind- H.S. initiated the project; V.S. and H.S. designed the experiments; V.S., A.O.-R., and 13 ing protein; RB1, retinoblastoma 1; R6K4, [ C6L-arginine/D4 L-lysine; R10K8, H.S. wrote the paper; V.S., I.H., C.B., and A.O.-R. performed the experiments; V.S., 13 15 13 15 [ C , N ]L-arginine/[ C , N ]L-lysine; RNAi, RNA interference; RPS6, ribosomal I.H., C.B., and A.O.-R. analyzed data; all authors read and approved the manuscript. 6 4 6 2 protein S6; shControl, short hairpin RNA control; shRNA, short hairpin RNA; The mass spectrometry proteomics data presented in this article have been deposited SILAC, stable isotope labeling with amino acids in cell culture; SPTBN1, spectrin to the ProteomeXchange Consortium via the PRIDE partner repository (https://www. b nonerythrocytic 1; STIM1, stromal interaction molecule 1; TiO2, titanium oxide; ebi.ac.uk/pride/archive/) with the dataset identifier PXD002055. VCP, valosin-containing protein. Address correspondence and reprint requests to Prof. Hannes Stockinger, Molecular Ó Immunology Unit, Institute for Hygiene and Applied Immunology, Kinderspitalgasse Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 15, 1090 Vienna, Austria. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600355 The Journal of Immunology 2469 and XIAP (21), an effect that is at least partially dependent on (shCD147) containing an shRNA construct specific for human CD147 and the MAPK activation (22). A possible link between CD147 and pBMN-IRES-GFP-HACD147etc containing the RNA interference (RNAi)- these pro- and anti-apoptotic regulators might lie in the CD147- resistant full-length CD147 with a hemagglutinin (HA)-tag (HACD147etc) were cloned as described previously (64). dependent activation of FAK and Src, which enhances heat shock 70 kDa protein 5 (HSPA5) promoter activity via the phosphorylation Gene transfer of TFII-I (17). Viral transduction was used for gene delivery, as documented elsewhere (66). In addition, CD147 also plays a crucial role in T cell biology:
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