Differential signaling by adaptor molecules LRP1 and ShcA regulates adipogenesis by the insulin-like growth factor-1 receptor

Estelle Woldt, Rachel L. Matz, Jérome Terrand, Mohamed Mlih, Céline Gracia, Sophie Foppolo, Sophie Martin, Véronique Bruban, Julie Ji, Emilie Velot, Joachim Herz, Philippe Boucher

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23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)16775-16782
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number19
DOIs
StatePublished - May 13 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Woldt, E., Matz, R. L., Terrand, J., Mlih, M., Gracia, C., Foppolo, S., Martin, S., Bruban, V., Ji, J., Velot, E., Herz, J., & Boucher, P. (2011). Differential signaling by adaptor molecules LRP1 and ShcA regulates adipogenesis by the insulin-like growth factor-1 receptor. Journal of Biological Chemistry, 286(19), 16775-16782. https://doi.org/10.1074/jbc.M110.212878