Journal
SCIENCE SIGNALING
Volume 2, Issue 68, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2000188
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Funding
- NINDS NIH HHS [R01 NS054671-02, R01 NS054671] Funding Source: Medline
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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 M-2) 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 M-2 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.
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