[{"volume":8,"date_created":"2023-09-06T08:07:51Z","article_type":"original","scopus_import":"1","day":"01","author":[{"last_name":"Alanko","id":"2CC12E8C-F248-11E8-B48F-1D18A9856A87","full_name":"Alanko, Jonna H","first_name":"Jonna H","orcid":"0000-0002-7698-3061"},{"last_name":"Ucar","id":"50B2A802-6007-11E9-A42B-EB23E6697425","full_name":"Ucar, Mehmet C","first_name":"Mehmet C","orcid":"0000-0003-0506-4217"},{"first_name":"Nikola","orcid":"0000-0002-8518-5926","full_name":"Canigova, Nikola","id":"3795523E-F248-11E8-B48F-1D18A9856A87","last_name":"Canigova"},{"id":"489E3F00-F248-11E8-B48F-1D18A9856A87","full_name":"Stopp, Julian A","last_name":"Stopp","first_name":"Julian A"},{"last_name":"Schwarz","full_name":"Schwarz, Jan","id":"346C1EC6-F248-11E8-B48F-1D18A9856A87","first_name":"Jan"},{"last_name":"Merrin","id":"4515C308-F248-11E8-B48F-1D18A9856A87","full_name":"Merrin, Jack","first_name":"Jack","orcid":"0000-0001-5145-4609"},{"orcid":"0000-0001-6005-1561","first_name":"Edouard B","last_name":"Hannezo","id":"3A9DB764-F248-11E8-B48F-1D18A9856A87","full_name":"Hannezo, Edouard B"},{"first_name":"Michael K","orcid":"0000-0002-6620-9179","last_name":"Sixt","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","full_name":"Sixt, Michael K"}],"oa_version":"Published Version","title":"CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration","publication_identifier":{"issn":["2470-9468"]},"publication_status":"published","abstract":[{"text":"Immune responses rely on the rapid and coordinated migration of leukocytes. Whereas it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how these gradients are generated, maintained, and modulated. By combining experimental data with theory on leukocyte chemotaxis guided by the G protein–coupled receptor (GPCR) CCR7, we demonstrate that in addition to its role as the sensory receptor that steers migration, CCR7 also acts as a generator and a modulator of chemotactic gradients. Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) effectively internalize the receptor and ligand as part of the canonical GPCR desensitization response. We show that CCR7 internalization also acts as an effective sink for the chemoattractant, dynamically shaping the spatiotemporal distribution of the chemokine. This mechanism drives complex collective migration patterns, enabling DCs to create or sharpen chemotactic gradients. We further show that these self-generated gradients can sustain the long-range guidance of DCs, adapt collective migration patterns to the size and geometry of the environment, and provide a guidance cue for other comigrating cells. Such a dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization.","lang":"eng"}],"intvolume":"         8","department":[{"_id":"MiSi"},{"_id":"EdHa"},{"_id":"NanoFab"}],"article_number":"adc9584","month":"09","citation":{"ama":"Alanko JH, Ucar MC, Canigova N, et al. CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. <i>Science Immunology</i>. 2023;8(87). doi:<a href=\"https://doi.org/10.1126/sciimmunol.adc9584\">10.1126/sciimmunol.adc9584</a>","ieee":"J. H. Alanko <i>et al.</i>, “CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration,” <i>Science Immunology</i>, vol. 8, no. 87. American Association for the Advancement of Science, 2023.","short":"J.H. Alanko, M.C. Ucar, N. Canigova, J.A. Stopp, J. Schwarz, J. Merrin, E.B. Hannezo, M.K. Sixt, Science Immunology 8 (2023).","chicago":"Alanko, Jonna H, Mehmet C Ucar, Nikola Canigova, Julian A Stopp, Jan Schwarz, Jack Merrin, Edouard B Hannezo, and Michael K Sixt. “CCR7 Acts as Both a Sensor and a Sink for CCL19 to Coordinate Collective Leukocyte Migration.” <i>Science Immunology</i>. American Association for the Advancement of Science, 2023. <a href=\"https://doi.org/10.1126/sciimmunol.adc9584\">https://doi.org/10.1126/sciimmunol.adc9584</a>.","ista":"Alanko JH, Ucar MC, Canigova N, Stopp JA, Schwarz J, Merrin J, Hannezo EB, Sixt MK. 2023. CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Science Immunology. 8(87), adc9584.","apa":"Alanko, J. H., Ucar, M. C., Canigova, N., Stopp, J. A., Schwarz, J., Merrin, J., … Sixt, M. K. (2023). CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. <i>Science Immunology</i>. American Association for the Advancement of Science. <a href=\"https://doi.org/10.1126/sciimmunol.adc9584\">https://doi.org/10.1126/sciimmunol.adc9584</a>","mla":"Alanko, Jonna H., et al. “CCR7 Acts as Both a Sensor and a Sink for CCL19 to Coordinate Collective Leukocyte Migration.” <i>Science Immunology</i>, vol. 8, no. 87, adc9584, American Association for the Advancement of Science, 2023, doi:<a href=\"https://doi.org/10.1126/sciimmunol.adc9584\">10.1126/sciimmunol.adc9584</a>."},"issue":"87","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa":1,"language":[{"iso":"eng"}],"_id":"14274","date_updated":"2023-12-21T14:30:01Z","type":"journal_article","article_processing_charge":"No","doi":"10.1126/sciimmunol.adc9584","publisher":"American Association for the Advancement of Science","main_file_link":[{"url":"https://doi.org/10.1126/sciimmunol.adc9584","open_access":"1"}],"quality_controlled":"1","keyword":["General Medicine","Immunology"],"year":"2023","isi":1,"related_material":{"record":[{"id":"14279","status":"public","relation":"research_data"},{"status":"public","relation":"dissertation_contains","id":"14697"}]},"external_id":{"isi":["001062110600003"],"pmid":["37656776"]},"ec_funded":1,"pmid":1,"date_published":"2023-09-01T00:00:00Z","acknowledgement":"We thank I. de Vries and the Scientific Service Units (Life Sciences, Bioimaging, Nanofabrication, Preclinical and Miba Machine Shop) of the Institute of Science and Technology Austria for excellent support, as well as all the rotation students assisting in the laboratory work (B. Zens, H. Schön, and D. Babic).\r\nThis work was supported by grants from the European Research Council under the European Union’s Horizon 2020 research to M.S. (grant agreement no. 724373) and to E.H. (grant agreement no. 851288), and a grant by the Austrian Science Fund (DK Nanocell W1250-B20) to M.S. J.A. was supported by the Jenny and Antti Wihuri Foundation and Research Council of Finland's Flagship Programme InFLAMES (decision number: 357910). M.C.U. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 754411.","status":"public","publication":"Science Immunology","project":[{"name":"Cellular navigation along spatial gradients","grant_number":"724373","call_identifier":"H2020","_id":"25FE9508-B435-11E9-9278-68D0E5697425"},{"_id":"05943252-7A3F-11EA-A408-12923DDC885E","grant_number":"851288","name":"Design Principles of Branching Morphogenesis","call_identifier":"H2020"},{"_id":"265E2996-B435-11E9-9278-68D0E5697425","name":"Nano-Analytics of Cellular Systems","grant_number":"W01250-B20","call_identifier":"FWF"},{"name":"ISTplus - Postdoctoral Fellowships","grant_number":"754411","call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425"}]},{"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"chicago":"Düllberg, Christian F, Albert Auer, Nikola Canigova, Katrin Loibl, and Martin Loose. “In Vitro Reconstitution Reveals Phosphoinositides as Cargo-Release Factors and Activators of the ARF6 GAP ADAP1.” <i>PNAS</i>. National Academy of Sciences, 2021. <a href=\"https://doi.org/10.1073/pnas.2010054118\">https://doi.org/10.1073/pnas.2010054118</a>.","ista":"Düllberg CF, Auer A, Canigova N, Loibl K, Loose M. 2021. In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1. PNAS. 118(1), e2010054118.","mla":"Düllberg, Christian F., et al. “In Vitro Reconstitution Reveals Phosphoinositides as Cargo-Release Factors and Activators of the ARF6 GAP ADAP1.” <i>PNAS</i>, vol. 118, no. 1, e2010054118, National Academy of Sciences, 2021, doi:<a href=\"https://doi.org/10.1073/pnas.2010054118\">10.1073/pnas.2010054118</a>.","apa":"Düllberg, C. F., Auer, A., Canigova, N., Loibl, K., &#38; Loose, M. (2021). In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1. <i>PNAS</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2010054118\">https://doi.org/10.1073/pnas.2010054118</a>","ama":"Düllberg CF, Auer A, Canigova N, Loibl K, Loose M. In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1. <i>PNAS</i>. 2021;118(1). doi:<a href=\"https://doi.org/10.1073/pnas.2010054118\">10.1073/pnas.2010054118</a>","short":"C.F. Düllberg, A. Auer, N. Canigova, K. Loibl, M. Loose, PNAS 118 (2021).","ieee":"C. F. Düllberg, A. Auer, N. Canigova, K. Loibl, and M. Loose, “In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1,” <i>PNAS</i>, vol. 118, no. 1. National Academy of Sciences, 2021."},"issue":"1","language":[{"iso":"eng"}],"oa":1,"article_number":"e2010054118","department":[{"_id":"MaLo"},{"_id":"MiSi"}],"month":"01","publication_status":"published","publication_identifier":{"eissn":["10916490"],"issn":["00278424"]},"acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"EM-Fac"}],"intvolume":"       118","abstract":[{"text":"The differentiation of cells depends on a precise control of their internal organization, which is the result of a complex dynamic interplay between the cytoskeleton, molecular motors, signaling molecules, and membranes. For example, in the developing neuron, the protein ADAP1 (ADP-ribosylation factor GTPase-activating protein [ArfGAP] with dual pleckstrin homology [PH] domains 1) has been suggested to control dendrite branching by regulating the small GTPase ARF6. Together with the motor protein KIF13B, ADAP1 is also thought to mediate delivery of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to the axon tip, thus contributing to PIP3 polarity. However, what defines the function of ADAP1 and how its different roles are coordinated are still not clear. Here, we studied ADAP1’s functions using in vitro reconstitutions. We found that KIF13B transports ADAP1 along microtubules, but that PIP3 as well as PI(3,4)P2 act as stop signals for this transport instead of being transported. We also demonstrate that these phosphoinositides activate ADAP1’s enzymatic activity to catalyze GTP hydrolysis by ARF6. Together, our results support a model for the cellular function of ADAP1, where KIF13B transports ADAP1 until it encounters high PIP3/PI(3,4)P2 concentrations in the plasma membrane. Here, ADAP1 disassociates from the motor to inactivate ARF6, promoting dendrite branching.","lang":"eng"}],"date_created":"2021-01-03T23:01:23Z","article_type":"original","volume":118,"oa_version":"Published Version","title":"In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1","scopus_import":"1","day":"05","author":[{"orcid":"0000-0001-6335-9748","first_name":"Christian F","last_name":"Düllberg","id":"459064DC-F248-11E8-B48F-1D18A9856A87","full_name":"Düllberg, Christian F"},{"id":"3018E8C2-F248-11E8-B48F-1D18A9856A87","full_name":"Auer, Albert","last_name":"Auer","first_name":"Albert","orcid":"0000-0002-3580-2906"},{"id":"3795523E-F248-11E8-B48F-1D18A9856A87","full_name":"Canigova, Nikola","last_name":"Canigova","orcid":"0000-0002-8518-5926","first_name":"Nikola"},{"last_name":"Loibl","full_name":"Loibl, Katrin","id":"3760F32C-F248-11E8-B48F-1D18A9856A87","first_name":"Katrin","orcid":"0000-0002-2429-7668"},{"first_name":"Martin","orcid":"0000-0001-7309-9724","last_name":"Loose","full_name":"Loose, Martin","id":"462D4284-F248-11E8-B48F-1D18A9856A87"}],"acknowledgement":"We thank Urban Bezeljak, Natalia Baranova, Mar Lopez-Pelegrin, Catarina Alcarva, and Victoria Faas for sharing reagents and helpful discussions. We thank Veronika Szentirmai for help with protein purifications. We thank Carrie Bernecky, Sascha Martens, and the M.L. lab for comments on the manuscript. We thank the bioimaging facility, the life science facility, and Armel Nicolas from the mass spec facility at the Institute of Science and Technology (IST) Austria for technical support. C.D. acknowledges funding from the IST fellowship program; this work was supported by Human Frontier Science Program Young Investigator Grant\r\nRGY0083/2016. ","date_published":"2021-01-05T00:00:00Z","pmid":1,"status":"public","publication":"PNAS","project":[{"_id":"2599F062-B435-11E9-9278-68D0E5697425","grant_number":"RGY0083/2016","name":"Reconstitution of cell polarity and axis determination in a cell-free system"}],"external_id":{"pmid":["33443153"],"isi":["000607270100018"]},"isi":1,"year":"2021","quality_controlled":"1","main_file_link":[{"url":"https://doi.org/10.1073/pnas.2010054118","open_access":"1"}],"type":"journal_article","_id":"8988","date_updated":"2023-08-04T11:20:46Z","publisher":"National Academy of Sciences","article_processing_charge":"No","doi":"10.1073/pnas.2010054118"}]