title: Differential signaling by adaptor molecules LRP1 and ShcA regulates adipogenesis by the insulin-like growth factor-1 receptor.
abstract: The low density lipoprotein receptor-related protein (LRP1) is a transmembrane receptor that integrates multiple signaling pathways. Its cytoplasmic domain serves as docking sites for several adaptor proteins such as the Src homology 2/α-collagen (ShcA), which also binds to several tyrosine kinase receptors such as the insulin-like growth factor 1 (IGF-1) receptor. However, the physiological significance of the physical interaction between LRP1 and ShcA, and whether this interaction modifies tyrosine kinase receptor signaling, are still unknown. Here we report that LRP1 forms a complex with the IGF-1 receptor, and that LRP1 is required for ShcA to become sensitive to IGF-1 stimulation. Upon IGF-1 treatment, ShcA is tyrosine phosphorylated and translocates to the plasma membrane only in the presence of LRP1. This leads to the recruitment of the growth factor receptor-bound protein 2 (Grb2) to ShcA, and activation of the Ras/MAP kinase pathway. Conversely, in the absence of ShcA, IGF-1 signaling bifurcates toward the Akt/mammalian target of rapamycin pathway and accelerates adipocyte differentiation when cells are stimulated for adipogenesis. These results establish the LRP1-ShcA complex as an essential component in the IGF-1-regulated pathway for MAP kinase and Akt/mammalian target of rapamycin activation, and may help to understand the IGF-1 signaling shift from clonal expansion to growth-arrested cells and differentiation during adipogenesis.
authors: CNRS, UMR7213, University of Strasbourg, Illkirch, F-67401 France.
authors: Estelle
authors: E
authors: Woldt
authors: Rachel L
authors: RL
authors: Matz
authors: Jérome
authors: J
authors: Terrand
authors: Mohamed
authors: M
authors: Mlih
authors: Céline
authors: C
authors: Gracia
authors: Sophie
authors: S
authors: Foppolo
authors: Sophie
authors: S
authors: Martin
authors: Véronique
authors: V
authors: Bruban
authors: Julie
authors: J
authors: Ji
authors: Emilie
authors: E
authors: Velot
authors: Joachim
authors: J
authors: Herz
authors: Philippe
authors: P
authors: Boucher
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002454:Cell Differentiation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry; D018631:ras Proteins / Q000378:metabolism
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins