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dc.contributor.authorMackie, Duncan I
dc.contributor.authorNielsen, Natalie R
dc.contributor.authorHarris, Matthew
dc.contributor.authorSingh, Smriti
dc.contributor.authorDavis, Reema B
dc.contributor.authorDy, Danica
dc.contributor.authorLadds, Graham
dc.contributor.authorCaron, Kathleen M
dc.date.accessioned2019-11-28T00:30:26Z
dc.date.available2019-11-28T00:30:26Z
dc.date.issued2019-11-26
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/299354
dc.description.abstractReceptor-activity-modifying proteins (RAMPs) are single transmembrane-spanning proteins which serve as molecular chaperones and allosteric modulators of G-protein-coupled receptors (GPCRs) and their signaling pathways. Although RAMPs have been previously studied in the context of their effects on Family B GPCRs, the coevolution of RAMPs with many GPCR families suggests an expanded repertoire of potential interactions. Using bioluminescence resonance energy transfer-based and cell-surface expression approaches, we comprehensively screen for RAMP interactions within the chemokine receptor family and identify robust interactions between RAMPs and nearly all chemokine receptors. Most notably, we identify robust RAMP interaction with atypical chemokine receptors (ACKRs), which function to establish chemotactic gradients for directed cell migration. Specifically, RAMP3 association with atypical chemokine receptor 3 (ACKR3) diminishes adrenomedullin (AM) ligand availability without changing G-protein coupling. Instead, RAMP3 is required for the rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following either AM or SDF-1/CXCL12 binding, thereby enabling formation of dynamic spatiotemporal chemotactic gradients. Consequently, genetic deletion of either ACKR3 or RAMP3 in mice abolishes directed cell migration of retinal angiogenesis. Thus, RAMP association with chemokine receptor family members represents a molecular interaction to control receptor signaling and trafficking properties.
dc.description.sponsorshipThis work was supported by NIH Grants RO1-DK099156, RO1-HD060860, and RO1-HL129086 (to K.M.C.); American Heart Association Innovator Award 16IRG27260077 (to K.M.C.); NIH Grant F32-HL134279 (to D.I.M.); American Heart Association Grant 15POST25270006 (to R.B.D.); NIH Grant F31-HL143836 (to N.R.N.); Biotechnology and Biological Sciences Research Council (BBSRC) Grant BB/M00015X/2 (to G.L.); and BBSRC Doctoral Training Partnership Grant BB/JO14540/1 (to M.H.).
dc.languageeng
dc.publisherNational Academy of Sciences
dc.rightsAll rights reserved
dc.subjectG-protein–coupled receptors
dc.subjectchemokine receptors
dc.subjectendosomal sorting
dc.subjectguided cell migration
dc.subjectreceptor-activity–modifying proteins
dc.titleRAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis.
dc.typeArticle
prism.endingPage24099
prism.issueIdentifier48
prism.publicationNameProceedings of the National Academy of Sciences of USA
prism.startingPage24093
prism.volume116
dc.identifier.doi10.17863/CAM.46423
dcterms.dateAccepted2019-10-21
rioxxterms.versionofrecord10.1073/pnas.1905561116
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-10-21
dc.contributor.orcidHarris, Matthew [0000-0002-7918-5735]
dc.contributor.orcidLadds, Graham [0000-0001-7320-9612]
dc.identifier.eissn1091-6490
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/M00015X/2)
pubs.funder-project-idBBSRC (1643678)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (1643678)
cam.issuedOnline2019-11-11
cam.orpheus.successThu Jan 30 10:36:17 GMT 2020 - Embargo updated
rioxxterms.freetoread.startdate2020-05-11


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