Journal article
Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
Proceedings of the National Academy of Sciences - PNAS, Vol.114(4), pp.752-757
01/24/2017
DOI: 10.1073/pnas.1620301114
PMCID: PMC5278494
PMID: 28069944
Abstract
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.
Details
- Title: Subtitle
- Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
- Creators
- George Dalton - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390Sung-Wan An - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390Saif I Al-Juboori - Department of Electrical Engineering, University of Colorado Denver, Denver, CO 80204Nicole Nischan - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390Joonho Yoon - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390Evgenia Dobrinskikh - Department of Medicine, University of Colorado Denver, Denver, CO 80204Donald W Hilgemann - Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390Jian Xie - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390Kate Luby-Phelps - Live Cell Imaging Core Facility, University of Texas Southwestern Medical Center, Dallas, TX 75390Jennifer J Kohler - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390Lutz Birnbaumer - Institute of Biomedical Research, School of Medical Sciences, Catholic University of Argentina, C1107AAZ Buenos Aires, ArgentinaChou-Long Huang - Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; chou-long.huang@utsouthwestern.edu Birnbau1@gmail.com
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.114(4), pp.752-757
- DOI
- 10.1073/pnas.1620301114
- PMID
- 28069944
- PMCID
- PMC5278494
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- R01 HL119843 / NHLBI NIH HHS UL1 TR001082 / NCATS NIH HHS R01 DK085726 / NIDDK NIH HHS Z01 ES101684 / Intramural NIH HHS R01 DK100605 / NIDDK NIH HHS R01 DK109887 / NIDDK NIH HHS
- Language
- English
- Date published
- 01/24/2017
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094216802771
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