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

• Autores: 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
• Año de publicación: 2017
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Proceedings of the National Academy of Sciences. 2017;114(4):752-757
• Materia: TUMORES; PROTEINAS; MEMBRANAS CELULARES; LIPIDOS
• Institución: Pontificia Universidad Católica Argentina

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.