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.