LRP: a bright beacon at the blood-brain barrier

Abstract

Ever more unexpected roles for the LDL receptor gene family in a variety of cellular signaling pathways continue to emerge. Three recent studies now add another function to this collection. By interacting with active tissue-type plasminogen activator, LDL receptor-related protein appears to control permeability of the blood-brain barrier, vascular tone, and the expression of MMPs. All of these parameters impact upon postischemic infarct size following stroke. These novel findings are discussed in the context of known mechanisms of signaling by the LDL receptor family.

Figure 1

Potential mechanisms of signaling by LRP. (a) Signaling through homotypic clustering. This mode of signaling has been reported to result in the activation of stress-activated protein kinase (SAPK, also known as p38). It involves clustering of LRP through, for example, binding of calreticulin to extracellular protein complexes or apoptotic debris (red circles) and may thereby function in the regulation of inflammation (13). Activation of PI3K and Erk through calreticulin ligation and potential roles in cell adhesion have also been reported (21). (b) Heterocomplex formation of LRP with the membrane tyrosine kinase receptor PDGFRβ modulates PDGFR signaling and controls the proliferation of VSMCs (11, 14). Phosphorylation (P) of the LRP ICD may function as a molecular switch that directs LRP toward endocytosis or mitogenic signaling. (c) Proteolytic processing of LRP by tPA or a tPA-dependent mechanism, followed by release of the ICD by intramembranous cleavage, analogous to the processing of Notch, may activate intracellular mechanisms, e.g., transcriptional regulation, translocation to sites of cellular adhesion, cytoskeletal rearrangements, etc.