Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling

George Dalton, Sung Wan An, Saif I. Al-Juboori, Nicole Nischan, Joonho Yoon, Evgenia Dobrinskikh, Donald W. Hilgemann, Jian Xie, Kate Luby-Phelps, Jennifer J. Kohler, Lutz Birnbaumer, Chou Long Huang

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)752-757
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number4
DOIs
StatePublished - Jan 24 2017

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Membrane Microdomains
Phosphatidylinositol 3-Kinases
Intercellular Signaling Peptides and Proteins
Lipids
Gangliosides
Polysaccharides
Down-Regulation
Sialic Acids
Membrane Lipids
Endocytosis
Cluster Analysis
Membrane Proteins
Membranes
sialogangliosides
Neoplasms
3'-sialyllactose

Keywords

  • Gangliosides
  • Lipid rafts
  • Sialic acids
  • Soluble klotho
  • TRPC6

ASJC Scopus subject areas

  • General

Cite this

Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 4, 24.01.2017, p. 752-757.

Research output: Contribution to journalArticle

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AU - Al-Juboori, Saif I.

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AU - Dobrinskikh, Evgenia

AU - Hilgemann, Donald W.

AU - Xie, Jian

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