Low-density lipoprotein receptor-related protein 1 (LRP1) functions in endocytosis and intracellular signaling for a variety of structurally diverse ligands. Although LRP1 has been implicated in several aspects of neuronal function, molecular mechanisms underlying the activity of neuronal LRP1 remain unclear. Here, we describe a signaling pathway whereby LRP1 transactivates Trk receptors. Binding of tissue-type plasminogen activator or alpha(2)-macroglobulin (alpha(2)M) to LRP1 resulted in Src family kinase (SFK) activation and SFK-dependent Trk receptor transactivation in PC12 cells and neurons. Trk receptor transactivation was necessary for activation of Akt and extracellular signal-regulated kinase and for neurite outgrowth downstream of LRP1. Injection of the LRP1-binding domain of alpha(2)M into rat dorsal root ganglia induced Trk receptor phosphorylation, which was blocked by receptor-associated protein, an antagonist of ligand binding to LRP1. Trk receptor transactivation provides a mechanism by which diverse LRP1 ligands may show neurotrophic activity.

Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway / Shi, Y; Mantuano, Elisabetta; Inoue, G; Campana, Wm; Gonias, S. L.. - In: SCIENCE SIGNALING. - ISSN 1937-9145. - STAMPA. - 2:68(2009), p. ra18. [10.1126/scisignal.2000188]

Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway.

MANTUANO, ELISABETTA;
2009

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) functions in endocytosis and intracellular signaling for a variety of structurally diverse ligands. Although LRP1 has been implicated in several aspects of neuronal function, molecular mechanisms underlying the activity of neuronal LRP1 remain unclear. Here, we describe a signaling pathway whereby LRP1 transactivates Trk receptors. Binding of tissue-type plasminogen activator or alpha(2)-macroglobulin (alpha(2)M) to LRP1 resulted in Src family kinase (SFK) activation and SFK-dependent Trk receptor transactivation in PC12 cells and neurons. Trk receptor transactivation was necessary for activation of Akt and extracellular signal-regulated kinase and for neurite outgrowth downstream of LRP1. Injection of the LRP1-binding domain of alpha(2)M into rat dorsal root ganglia induced Trk receptor phosphorylation, which was blocked by receptor-associated protein, an antagonist of ligand binding to LRP1. Trk receptor transactivation provides a mechanism by which diverse LRP1 ligands may show neurotrophic activity.
NF-KAPPA-B, FOCAL ADHESION KINASE, NERVE GROWTH-FACTOR, SIGNAL-TRANSDUCTION, CELL-MIGRATION, SCHWANN-CELLS, HUMAN ALPHA(2)-MACROGLOBULIN, HUMAN ALPHA-2-MACROGLOBULIN, GENE-EXPRESSION, PROTEIN-KINASE
01 Pubblicazione su rivista::01a Articolo in rivista
Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway / Shi, Y; Mantuano, Elisabetta; Inoue, G; Campana, Wm; Gonias, S. L.. - In: SCIENCE SIGNALING. - ISSN 1937-9145. - STAMPA. - 2:68(2009), p. ra18. [10.1126/scisignal.2000188]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/769670
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