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

Mostrar todas las versiones(2)

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 lif...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Artículo
Lenguaje:Inglés
Publicado: National Academy of Sciences 2019
Materias:
TUMORES
PROTEINAS
MEMBRANAS CELULARES
LIPIDOS
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/8734
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139-123456789-8734
record_format dspace
spelling I33-R139-123456789-87342024-03-26T10:33:23Z 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 TUMORES PROTEINAS MEMBRANAS CELULARES LIPIDOS 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. 2019-09-12T20:07:24Z 2019-09-12T20:07:24Z 2017 Artículo 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: https://repositorio.uca.edu.ar/handle/123456789/8734 0027-8424 1091-6490 (online) https://repositorio.uca.edu.ar/handle/123456789/8734 10.1073/pnas.1620301114 28069944 eng Acceso Abierto http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf National Academy of Sciences Proceedings of the National Academy of Sciences. 2017;114(4):752-757
institution Universidad Católica Argentina
institution_str I-33
repository_str R-139
collection Repositorio Institucional de la Universidad Católica Argentina (UCA)
language Inglés
topic TUMORES
PROTEINAS
MEMBRANAS CELULARES
LIPIDOS
spellingShingle TUMORES
PROTEINAS
MEMBRANAS CELULARES
LIPIDOS
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
Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
topic_facet TUMORES
PROTEINAS
MEMBRANAS CELULARES
LIPIDOS
description 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.
format Artículo
author 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
author_facet 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
author_sort Dalton, George
title Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_short Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_full Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_fullStr Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_full_unstemmed Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_sort soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
publisher National Academy of Sciences
publishDate 2019
url https://repositorio.uca.edu.ar/handle/123456789/8734
work_keys_str_mv AT daltongeorge solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT ansungwan solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT aljuboorisaifi solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT nischannicole solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT yoonjoonho solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT dobrinskikhevgenia solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT hilgemanndonaldw solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT xiejian solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT lubyphelpskate solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT kohlerjenniferj solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT birnbaumerlutz solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
AT huangchoulong solubleklothobindsmonosialogangliosidetoregulatemembranemicrodomainsandgrowthfactorsignaling
_version_ 1807949082475364352

Ejemplares similares