Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 25 November 2008
Vol. 1, Issue 47, p. ra15
[DOI: 10.1126/scisignal.1164263]


Editor's Summary

Feedback Required
Inflammatory responses, such as those elicited by bacterial lipopolysaccharide (LPS), are critical for clearance of infection, but these responses must then be reined in to prevent the occurrence of side effects such as tissue damage. Low-density lipoprotein receptor–related protein 1 (LRP1) is a multifunctional lipoprotein receptor that plays a role in endocytosis and signal transduction. Processing of LRP1 by the {gamma}-secretase complex releases the intracellular domain (ICD) of LRP1 from the plasma membrane. Zurhove et al. now show that LPS-stimulated processing of LRP1 by {gamma}-secretase results in ICD-mediated feedback inhibition of the inflammatory response, in part by inhibiting the activity of the transcription factor interferon regulatory factor 3. As well as linking {gamma}-secretase and LRP1 to the innate immune response, these data are potentially of clinical relevance; the therapeutic use of {gamma}-secretase inhibitors may have the undesirable outcome of shutting down a pathway that prevents uncontrollable inflammation.

Citation: K. Zurhove, C. Nakajima, J. Herz, H. H. Bock, P. May, {gamma}-Secretase Limits the Inflammatory Response Through the Processing of LRP1. Sci. Signal. 1, ra15 (2008).

Read the Full Text

Low-Density Lipoprotein Receptor-Related Protein-1: Role in the Regulation of Vascular Integrity.
D. K. Strickland, D. T. Au, P. Cunfer, and S. C. Muratoglu (2014)
Arterioscler Thromb Vasc Biol 34, 487-498
   Abstract »    Full Text »    PDF »
Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Modulates N-Methyl-D-aspartate (NMDA) Receptor-dependent Intracellular Signaling and NMDA-induced Regulation of Postsynaptic Protein Complexes.
C. Nakajima, A. Kulik, M. Frotscher, J. Herz, M. Schafer, H. H. Bock, and P. May (2013)
J. Biol. Chem. 288, 21909-21923
   Abstract »    Full Text »    PDF »
Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris.
A. Fernandez-Castaneda, S. Arandjelovic, T. L. Stiles, R. K. Schlobach, K. A. Mowen, S. L. Gonias, and A. Gaultier (2013)
J. Biol. Chem. 288, 4538-4548
   Abstract »    Full Text »    PDF »
Neurovascular Dysfunction and Faulty Amyloid {beta}-Peptide Clearance in Alzheimer Disease.
A. P. Sagare, R. D. Bell, and B. V. Zlokovic (2012)
Cold Spring Harb Perspect Med 2, a011452
   Abstract »    Full Text »    PDF »
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease.
D. M. Holtzman, J. Herz, and G. Bu (2012)
Cold Spring Harb Perspect Med 2, a006312
   Abstract »    Full Text »    PDF »
Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages.
M. Gorovoy, A. Gaultier, W. M. Campana, G. S. Firestein, and S. L. Gonias (2010)
J. Leukoc. Biol. 88, 769-778
   Abstract »    Full Text »    PDF »
Pro-cathepsin D interacts with the extracellular domain of the {beta} chain of LRP1 and promotes LRP1-dependent fibroblast outgrowth.
M. Beaujouin, C. Prebois, D. Derocq, V. Laurent-Matha, O. Masson, S. Pattingre, P. Coopman, N. Bettache, J. Grossfield, R. E. Hollingsworth, et al. (2010)
J. Cell Sci. 123, 3336-3346
   Abstract »    Full Text »    PDF »
Nontraditional Signaling Mechanisms of Lipoprotein Receptors.
G. W. Rebeck (2009)
Science Signaling 2, pe28
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 25 November 2008.
P. May and A. M. VanHook (2008)
Science Signaling 1, pc12
   Abstract »    Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882