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Selective recruitme...
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Zheng, HYKarolinska Institutet
(författare)
Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor
- Artikel/kapitelEngelska2012
Förlag, utgivningsår, omfång ...
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2012-04-16
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Proceedings of the National Academy of Sciences,2012
Nummerbeteckningar
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LIBRIS-ID:oai:prod.swepub.kib.ki.se:124514781
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http://kipublications.ki.se/Default.aspx?queryparsed=id:124514781URI
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https://doi.org/10.1073/pnas.1118359109DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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β-Arrestins are multifunctional proteins that play central roles in G protein-coupled receptor (GPCR) trafficking and signaling. β-Arrestin1 is also recruited to the insulin-like growth factor-1 receptor (IGF-1R), a receptor tyrosine kinase (RTK), mediating receptor degradation and signaling. Because GPCR phosphorylation by GPCR-kinases (GRKs) governs interactions of the receptors with β-arrestins, we investigated the regulatory roles of the four widely expressed GRKs on IGF-1R signaling/degradation. By suppressing GRK expression with siRNA, we demonstrated that lowering GRK5/6 abolishes IGF1-mediated ERK and AKT activation, whereas GRK2 inhibition increases ERK activation and partially inhibits AKT signaling. Conversely, β-arrestin–mediated ERK signaling is enhanced by overexpression of GRK6 and diminished by GRK2. Similarly, we demonstrated opposing effects of GRK2 and -6 on IGF-1R degradation: GRK2 decreases whereas GRK6 enhances ligand-induced degradation. GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R, and subsequent mutation analysis demonstrated clear effects on IGF-1R signaling and degradation, mirroring alterations by GRKs. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation, consistent with GRK isoform-specific serine phosphorylation. This study demonstrates distinct roles for GRK isoforms in IGF-1R signaling through β-arrestin binding with divergent functional outcomes.
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Worrall, CKarolinska Institutet
(författare)
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Shen, HC
(författare)
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Issad, T
(författare)
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Seregard, SKarolinska Institutet
(författare)
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Girnita, AKarolinska Institutet
(författare)
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Girnita, LKarolinska Institutet
(författare)
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Karolinska Institutet
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences109:18, s. 7055-70601091-6490
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Ingår i:Proceedings of the National Academy of Sciences: Proceedings of the National Academy of Sciences109:18, s. 7055-70600027-8424
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