title: Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling.
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.
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: George
authors.initials: G
authors.lastname: Dalton
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Sung-Wan
authors.initials: SW
authors.lastname: An
authors.affiliation: Department of Electrical Engineering, University of Colorado Denver, Denver, CO 80204.
authors.forename: Saif I
authors.initials: SI
authors.lastname: Al-Juboori
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Nicole
authors.initials: N
authors.lastname: Nischan
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Joonho
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Department of Medicine, University of Colorado Denver, Denver, CO 80204.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Dobrinskikh
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Hilgemann
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Live Cell Imaging Core Facility, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Kate
authors.initials: K
authors.lastname: Luby-Phelps
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kohler
authors.affiliation: Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; chou-long.huang@utsouthwestern.edu Birnbau1@gmail.com.|Institute of Biomedical Research, School of Medical Sciences, Catholic University of Argentina, C1107AAZ Buenos Aires, Argentina.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; chou-long.huang@utsouthwestern.edu Birnbau1@gmail.com.
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D005732:Gangliosides / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000090265:Klotho Proteins; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D005732:Gangliosides; D005966:Glucuronidase; D036341:Intercellular Signaling Peptides and Proteins; D000090265:Klotho Proteins; D019869:Phosphatidylinositol 3-Kinases; C025447:sialogangliosides
keywords: TRPC6; gangliosides; lipid rafts; sialic acids; soluble klotho