Editors' ChoiceReceptors

Cleaved Into Action

See allHide authors and affiliations

Science's STKE  28 May 2002:
Vol. 2002, Issue 134, pp. tw189
DOI: 10.1126/stke.2002.134.tw189

The low density lipoprotein receptor-related protein (LRP) is a membrane-spanning receptor that binds a number of ligands and is implicated in internalization of ligands by endocytosis. The receptor also interacts with intracellular signaling proteins that may contribute to its varied biological roles, which include effects on neuronal development and neurodegeneration. Because the extracellular domain of LRP, like that of the receptor Notch, is cleaved by metalloproteinases, Hay et al. investigated whether the intracellular portion of the receptor might also be cleaved (like that of Notch and other receptors) by a different protease to mobilize signaling to the nucleus. They constructed a chimeric protein of LRP fused at the cytoplasmic COOH-terminus to a yeast Gal4 DNA-binding domain and a VP16 transactivation domain from herpes simplex virus. A reporter gene was used to monitor release of the cytoplasmic portion of the receptor, which was sensitive to inhibitors of γ-secretase and was enhanced by treatment of cells with phorbol myristate acetate to activate protein kinase C. The cytoplasmic portion of LRP has binding sites for adaptor and scaffold proteins; expression of the scaffolding protein FE65 or the adaptor Dab1 appeared to modulate processing of the receptor. Whether the receptor fragment signals in the cytoplasm or acts in the nucleus as do transcriptional activators released from sterol regulatory element-binding proteins remains to be determined.

P. May, Y. K. Reddy, J. Herz, Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J. Biol. Chem. 277, 18736-18743 (2002). [Abstract] [Full Text]

Stay Connected to Science Signaling