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Título : Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
Autor : Dalton, George 
An, Sung-Wan 
Al-Juboori, Saif I. 
Nischan, Nicole 
Yoon, Joonho 
Dobrinskikh, Evgenia 
Hilgemann, Donald W. 
Xie, Jian 
Luby-Phelps, Kate 
Kohler, Jennifer J. 
Birnbaumer, Lutz 
Huang, Chou-Long 
Fecha de publicación : 2017
Editorial : National Academy of Sciences
Cita : Dalton G, An S-W, Al-Juboori SI, et al. Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proceedings of the National Academy of Sciences. 2017;114(4):752-757. doi:10.1073/pnas.1620301114 Disponible en:
Resumen : 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.
ISSN : 0027-8424
1091-6490 (online)
Disciplina: MEDICINA
DOI: 10.1073/pnas.1620301114
Derechos: Acceso Abierto
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