Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation.
Fiche publication
Date publication
mars 2016
Journal
The Journal of biological chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Mme SCHAEFFER-REISS Christine, Dr VAN DORSSELAER Alain
Tous les auteurs :
El Asmar Z, Terrand J, Jenty M, Host L, Mlih M, Zerr A, Justiniano H, Matz RL, Boudier C, Scholler E, Garnier JM, Bertaccini D, Thiersé D, Schaeffer C, Van Dorsselaer A, Herz J, Bruban V, Boucher P
Lien Pubmed
Résumé
The low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell surface receptor that protects from intracellular cholesterol accumulation. However, the underlying mechanisms are unknown. Here we show that the extracellular (α) chain of LRP1 mediates TGFβ-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic (β) chain of LRP1 suffices to limit cholesterol accumulation in LRP1(-/-) cells. Through binding of Erk2 to the second of its carboxyl-terminal NPXY motifs, LRP1 β-chain positively regulates the expression of ATP binding cassette transporter A1 (ABCA1) and of neutral cholesterol ester hydrolase (NCEH1). These results highlight the unexpected functions of LRP1 and the canonical Wnt5a pathway and new therapeutic potential in cholesterol-associated disorders including cardiovascular diseases.
Mots clés
ATP Binding Cassette Transporter 1, metabolism, Amino Acid Sequence, Animals, Cholesterol, metabolism, HEK293 Cells, Humans, Mice, Mitogen-Activated Protein Kinase 1, metabolism, Molecular Sequence Data, Protein Structure, Tertiary, Receptors, LDL, chemistry, Sterol Esterase, metabolism, Transforming Growth Factor beta, metabolism, Tumor Suppressor Proteins, chemistry, Wnt Proteins, metabolism, Wnt Signaling Pathway, Wnt-5a Protein
Référence
J. Biol. Chem.. 2016 Mar;291(10):5116-27