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

Autor: George D. Dalton, Nicole Nischan, Evgenia Dobrinskikh, Joonho Yoon, Donald W. Hilgemann, Jennifer J. Kohler, Lutz Birnbaumer, Katherine Luby-Phelps, Saif I. Al-Juboori, Jian Xie, Sung Wan An, Chou Long Huang
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
GANGLIOSIDES
CIENCIAS MÉDICAS Y DE LA SALUD
Inmunología
TRPC6
Biology
urologic and male genital diseases
Endocytosis
Biophysical Phenomena
LIPIDOS
Cell Line
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Paracrine signalling
Membrane Microdomains
Cell Line
Tumor
Gangliosides
Animals
Humans
Klotho Proteins
Protein kinase B
Lipid raft
Klotho
PI3K/AKT/mTOR pathway
SOLUBLE KLOTHO
Glucuronidase
TUMORES
MEMBRANAS CELULARES
Multidisciplinary
030102 biochemistry & molecular biology
SIALIC ACIDS
PROTEINAS
purl.org/becyt/ford/3.1 [https]
Biological Sciences
humanities
female genital diseases and pregnancy complications
Cell biology
Medicina Básica
LIPID RAFTS
HEK293 Cells
030104 developmental biology
Ectodomain
Membrane protein
Intercellular Signaling Peptides and Proteins
lipids (amino acids
peptides
and proteins)
purl.org/becyt/ford/3 [https]
HeLa Cells
Signal Transduction
Zdroj: Proceedings of the National Academy of Sciences. 2017;114(4):752-757
CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
Repositorio Institucional (UCA)
Pontificia Universidad Católica Argentina
instacron:UCA
Popis: Fil: Dalton, George. University of Texas Southwestern Medical Center. Department of Medicine; Estados Unidos Fil: An, Sung-Wan. University of Texas Southwestern Medical Center. Department of Medicine; Estados Unidos Fil: Al-Juboori, Saif I. University of Colorado Denver. Department of Electrical Engineering; Estados Unidos Fil: Nischan, Nicole. University of Texas Southwestern Medical Center. Department of Biochemistry; Estados Unidos Fil: Yoon, Joonho. University of Texas Southwestern Medical Center. Department of Medicine; Estados Unidos Fil: Dobrinskikh, Evgenia. University of Colorado Denver. Department of Medicine; Estados Unidos Fil: Hilgemann, Donald W. University of Texas Southwestern Medical Center. Department of Physiology; Estados Unidos Fil: Xie, Jian. University of Texas Southwestern Medical Center. Department of Medicine; Estados Unidos Fil: Luby-Phelps, Kate. University of Texas Southwestern Medical Center. Department of Cell Biology; Estados Unidos Fil: Luby-Phelps, Kate. University of Texas Southwestern Medical Center. Live Cell Imaging Core Facility; Estados Unidos Fil: Kohler, Jennifer J. University of Texas Southwestern Medical Center. Department of Biochemistry; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos Fil: Huang, Chou-Long. University of Texas Southwestern Medical Center. Department of Medicine; Estados Unidos 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.
Databáze: OpenAIRE
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