The LDL receptor-related protein 1 (LRP1) is a type-1 transmembrane endocytic receptor originally identified as a ligand scavenger. The LRP1 precursor peptide is cleaved by the protease furin and transported to the plasma membrane as a two-chain molecule consisting of a 515-kDa extracellular α-chain and a transmembrane 85-kDa β-chain. The α-chain possesses four binding clusters that interact with multiple extracellular ligands and cell surface receptors involved in pericellular proteolysis, cell adhesion, motility and survival. The β-chain distal NPxYxxL sequence regulates clathrin-mediated endocytosis and recycling of LRP1 while both the proximal and distal NPxY motifs provide docking sites for several signaling adaptors and their accessory kinases. The LRP1 intracellular domain is also a platform for MAP kinases (ERK, JNK) that promote cell migration. LRP1-mediated endocytosis of CD44, moreover, regulates cell-ECM adhesion in carcinomas while the β-chain NPVY site integrates the extracellular HSP90α motility signal that involves Akt kinase. Although the molecular basis for the motile response to LRP1 engagement is unclear, binding of protease nexin-1 to LRP1 engages an ERK-dependent pathway that stimulates MMP-2 and MMP-9 expression. LRP1 interaction with plasminogen activators, their cellular receptors and plasminogen activator inhibitor PAI-1 provides additional controls on pericellular proteolysis, cell adhesion, migration, and survival. Binding of active, latent, or cleaved PAI-1 to LRP1 triggers Jak/Stat signaling resulting in a migratory phenotype suggesting a functional role for LRP1 apart from just proteolytic control. PAI-1 also induces Akt activation, at least in certain cell types. Increased pAkt levels upon PAI-1 stimulation is not evident in LRP1-/- fibroblasts and effectively blocked in LRP1+/+ cells by prior addition of RAP, which inhibits binding of all ligands to LRP1. Since LRP1 engagement initiates a variety of intracellular signaling events, the palette of LRP1 functions is more complex than its previous restriction as simply an endocytic clearance receptor.
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