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Sci. Signal., 28 April 2009
Vol. 2, Issue 68, p. ra18
[DOI: 10.1126/scisignal.2000188]

RESEARCH

Ligand Binding to LRP1 Transactivates Trk Receptors by a Src Family Kinase–Dependent Pathway

Yang Shi1, Elisabetta Mantuano1,2, Gen Inoue2,3, W. Marie Campana2, and Steven L. Gonias1*

1 Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0612, USA.
2 Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA.
3 Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, 260-8677 Japan.

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}2M) 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}2M 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.

* To whom correspondence should be addressed. E-mail: sgonias{at}ucsd.edu

Citation: Y. Shi, E. Mantuano, G. Inoue, W. M. Campana, S. L. Gonias, Ligand Binding to LRP1 Transactivates Trk Receptors by a Src Family Kinase–Dependent Pathway. Sci. Signal. 2, ra18 (2009).

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