Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane's propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:114 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 114(2017), 4 vom: 24. Jan., Seite 752-757 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dalton, George [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.04.2018 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1620301114 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM267834934 |
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| 100 | 1 | |a Dalton, George |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling |
| 264 | 1 | |c 2017 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane's propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a TRPC6 | |
| 650 | 4 | |a gangliosides | |
| 650 | 4 | |a lipid rafts | |
| 650 | 4 | |a sialic acids | |
| 650 | 4 | |a soluble klotho | |
| 650 | 7 | |a Gangliosides |2 NLM | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a sialogangliosides |2 NLM | |
| 650 | 7 | |a Glucuronidase |2 NLM | |
| 650 | 7 | |a EC 3.2.1.31 |2 NLM | |
| 650 | 7 | |a Klotho Proteins |2 NLM | |
| 650 | 7 | |a EC 3.2.1.31 |2 NLM | |
| 700 | 1 | |a An, Sung-Wan |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Juboori, Saif I |e verfasserin |4 aut | |
| 700 | 1 | |a Nischan, Nicole |e verfasserin |4 aut | |
| 700 | 1 | |a Yoon, Joonho |e verfasserin |4 aut | |
| 700 | 1 | |a Dobrinskikh, Evgenia |e verfasserin |4 aut | |
| 700 | 1 | |a Hilgemann, Donald W |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Luby-Phelps, Kate |e verfasserin |4 aut | |
| 700 | 1 | |a Kohler, Jennifer J |e verfasserin |4 aut | |
| 700 | 1 | |a Birnbaumer, Lutz |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Chou-Long |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.1620301114 |3 Volltext |
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