---
_id: '14274'
abstract:
- lang: eng
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.
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."
article_number: adc9584
article_processing_charge: No
article_type: original
author:
- first_name: Jonna H
full_name: Alanko, Jonna H
id: 2CC12E8C-F248-11E8-B48F-1D18A9856A87
last_name: Alanko
orcid: 0000-0002-7698-3061
- first_name: Mehmet C
full_name: Ucar, Mehmet C
id: 50B2A802-6007-11E9-A42B-EB23E6697425
last_name: Ucar
orcid: 0000-0003-0506-4217
- first_name: Nikola
full_name: Canigova, Nikola
id: 3795523E-F248-11E8-B48F-1D18A9856A87
last_name: Canigova
orcid: 0000-0002-8518-5926
- first_name: Julian A
full_name: Stopp, Julian A
id: 489E3F00-F248-11E8-B48F-1D18A9856A87
last_name: Stopp
- first_name: Jan
full_name: Schwarz, Jan
id: 346C1EC6-F248-11E8-B48F-1D18A9856A87
last_name: Schwarz
- first_name: Jack
full_name: Merrin, Jack
id: 4515C308-F248-11E8-B48F-1D18A9856A87
last_name: Merrin
orcid: 0000-0001-5145-4609
- first_name: Edouard B
full_name: Hannezo, Edouard B
id: 3A9DB764-F248-11E8-B48F-1D18A9856A87
last_name: Hannezo
orcid: 0000-0001-6005-1561
- first_name: Michael K
full_name: Sixt, Michael K
id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87
last_name: Sixt
orcid: 0000-0002-6620-9179
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. Science Immunology.
2023;8(87). doi:10.1126/sciimmunol.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. Science Immunology. American Association
for the Advancement of Science. https://doi.org/10.1126/sciimmunol.adc9584
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.” Science
Immunology. American Association for the Advancement of Science, 2023. https://doi.org/10.1126/sciimmunol.adc9584.
ieee: J. H. Alanko et al., “CCR7 acts as both a sensor and a sink for CCL19
to coordinate collective leukocyte migration,” Science Immunology, vol.
8, no. 87. American Association for the Advancement of Science, 2023.
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.
mla: Alanko, Jonna H., et al. “CCR7 Acts as Both a Sensor and a Sink for CCL19 to
Coordinate Collective Leukocyte Migration.” Science Immunology, vol. 8,
no. 87, adc9584, American Association for the Advancement of Science, 2023, doi:10.1126/sciimmunol.adc9584.
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).
date_created: 2023-09-06T08:07:51Z
date_published: 2023-09-01T00:00:00Z
date_updated: 2023-12-21T14:30:01Z
day: '01'
department:
- _id: MiSi
- _id: EdHa
- _id: NanoFab
doi: 10.1126/sciimmunol.adc9584
ec_funded: 1
external_id:
isi:
- '001062110600003'
pmid:
- '37656776'
intvolume: ' 8'
isi: 1
issue: '87'
keyword:
- General Medicine
- Immunology
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1126/sciimmunol.adc9584
month: '09'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 25FE9508-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '724373'
name: Cellular navigation along spatial gradients
- _id: 05943252-7A3F-11EA-A408-12923DDC885E
call_identifier: H2020
grant_number: '851288'
name: Design Principles of Branching Morphogenesis
- _id: 265E2996-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: W01250-B20
name: Nano-Analytics of Cellular Systems
- _id: 260C2330-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '754411'
name: ISTplus - Postdoctoral Fellowships
publication: Science Immunology
publication_identifier:
issn:
- 2470-9468
publication_status: published
publisher: American Association for the Advancement of Science
quality_controlled: '1'
related_material:
record:
- id: '14279'
relation: research_data
status: public
- id: '14697'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte
migration
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 8
year: '2023'
...
---
_id: '8988'
abstract:
- lang: eng
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.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
- _id: EM-Fac
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. "
article_number: e2010054118
article_processing_charge: No
article_type: original
author:
- first_name: Christian F
full_name: Düllberg, Christian F
id: 459064DC-F248-11E8-B48F-1D18A9856A87
last_name: Düllberg
orcid: 0000-0001-6335-9748
- first_name: Albert
full_name: Auer, Albert
id: 3018E8C2-F248-11E8-B48F-1D18A9856A87
last_name: Auer
orcid: 0000-0002-3580-2906
- first_name: Nikola
full_name: Canigova, Nikola
id: 3795523E-F248-11E8-B48F-1D18A9856A87
last_name: Canigova
orcid: 0000-0002-8518-5926
- first_name: Katrin
full_name: Loibl, Katrin
id: 3760F32C-F248-11E8-B48F-1D18A9856A87
last_name: Loibl
orcid: 0000-0002-2429-7668
- first_name: Martin
full_name: Loose, Martin
id: 462D4284-F248-11E8-B48F-1D18A9856A87
last_name: Loose
orcid: 0000-0001-7309-9724
citation:
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. PNAS. 2021;118(1). doi:10.1073/pnas.2010054118
apa: Düllberg, C. F., 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. National Academy of Sciences. https://doi.org/10.1073/pnas.2010054118
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.” PNAS. National Academy of
Sciences, 2021. https://doi.org/10.1073/pnas.2010054118.
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,” PNAS, vol. 118, no. 1. National Academy of Sciences, 2021.
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.” PNAS, vol.
118, no. 1, e2010054118, National Academy of Sciences, 2021, doi:10.1073/pnas.2010054118.
short: C.F. Düllberg, A. Auer, N. Canigova, K. Loibl, M. Loose, PNAS 118 (2021).
date_created: 2021-01-03T23:01:23Z
date_published: 2021-01-05T00:00:00Z
date_updated: 2023-08-04T11:20:46Z
day: '05'
department:
- _id: MaLo
- _id: MiSi
doi: 10.1073/pnas.2010054118
external_id:
isi:
- '000607270100018'
pmid:
- '33443153'
intvolume: ' 118'
isi: 1
issue: '1'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1073/pnas.2010054118
month: '01'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 2599F062-B435-11E9-9278-68D0E5697425
grant_number: RGY0083/2016
name: Reconstitution of cell polarity and axis determination in a cell-free system
publication: PNAS
publication_identifier:
eissn:
- '10916490'
issn:
- '00278424'
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
scopus_import: '1'
status: public
title: In vitro reconstitution reveals phosphoinositides as cargo-release factors
and activators of the ARF6 GAP ADAP1
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 118
year: '2021'
...