The low-density lipoprotein receptor-related protein (LRP) is a large, highly conserved receptor that binds numerous types of ligands, invokes several different signal transduction pathways, and is implicated in a variety of diseases including Alzheimer's disease, cancer, and HIV.1-9 LRP is a member of the low-density lipoprotein receptor (LDLR) family, which also includes apoliprotein E (ApoE) receptor 2, very low-density lipoprotein (VLDL) receptor, megalin, LRP5, LRP6, and LDLR. LRP was first cloned by virtue of its homology to LDLR.1 LRP is one of the largest members of the LDLR family. It is synthesized as a 600 kDa precursor protein and processed in the trans-Golgi by a furin-like protease to yield a 515 kDa alpha-chain and an 85 kDa beta-chain that associate non-covalently.1,2 The alpha-chain contains four ligand binding domains, commonly referred to as clusters I-IV9 that consist of different numbers of complement-type repeats.10 The beta-chain is composed of ligand binding complement-type and EGF receptor-like cysteine-rich repeats, YWTD domains, a single transmembrane domain, and a cytoplasmic region containing one or more NPxY motifs.3
|Table 1. LRP ligands and ligand binding sites.
|Table 2. LRP signaling events and downstream effects.
LRP is a multifunctional endocytotic receptor responsible for binding and internalizing a broad spectrum of structurally unrelated ligands including lipoproteins, proteinases, proteinase inhibitor complexes, extracellular matrix proteins, bacterial toxins, and viruses.3 Proteinases and molecules associated with regulating proteolytic activity comprise the largest group of the more than 30 ligands known to bind LRP. Several serine proteinases and metalloproteinases directly bind to LRP, while other proteins bind only after forming a complex with specific inhibitors. Many members of the Serpin superfamily of serine proteinase inhibitors only bind LRP after they have undergone conformational changes.3 Several studies utilizing recombinant "mini-receptors" have tested the affinities of particular known ligands for the ligand binding clusters (see Table 1). Clusters II and IV bind the largest number including a2M, ApoE, Factor VIII, Lactoferrin, LpL, PAI-1, pro-uPA, RAP, the tPA/PAI-1 complex, and the uPA/PAI-1 complex. RAP is the only ligand that appears to bind with high affinity to Cluster III and no ligands have been formed that bind Cluster I. 10-12
A large number of intracellular proteins interact with the cytoplasmic tail of LRP involving it in several different signaling pathways (see Table 2). LRP undergoes both serine and tyrosine phosphorylation under a variety of conditions.4,13 Serine phosphorylation regulates LRP internalization.4,13 Tyrosine phosphorylated LRP associates with the Src-homology 2 (SH2) domain containing Shc. Shc acts with Grb2 and Sos to activate Ras, an important event in cell division, differentiation, immune function regulation, and development.4 Disabled and FE65, two neuronal adaptor proteins involved in signaling, also bind LRP.4
LRP signaling may involve homo- and/or heterodimerization possibly resulting in the phosphorylation of NPxY motifs.4 Recently, a new mode of signaling was ascribed to LRP. Evidence suggests that the intracellular domain of LRP is cleaved by a protein kinase C-regulated gamma-secretase-like protease. The resulting LRP C-terminal fragment translocates to different subcellular compartments depending on the particular subset of regulatory proteins bound to it.14
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