Regulation of tumor necrosis factor receptor-1 and the IKK-NF-κB pathway by LDL receptor–related protein explains the antiinflammatory activity of this receptor

Abstract

Low-density lipoprotein receptor-related protein (LRP-1) functions in endocytosis and in cell signaling directly (by binding signaling adaptor proteins) or indirectly (by regulating levels of other cell-surface receptors). Because recent studies in rodents suggest that LRP-1 inhibits inflammation, we conducted activity-based protein profiling experiments to discover novel proteases, involved in inflammation, that are regulated by LRP-1. We found that activated complement proteases accumulate at increased levels when LRP-1 is absent. Although LRP-1 functions as an endocytic receptor for IntroductionLow-density lipoprotein (LDL) receptor-related protein (LRP-1) is a member of the LDL receptor gene family, which includes type I transmembrane proteins that function in receptor-mediated endocytosis and cell signaling. 1 LRP-1 was first recognized as a receptor for apolipoprotein E and for the protease inhibitor, ␣ 2 -macroglobulin (␣ 2 M) 2,3 ; however, it is now clear that LRP-1 binds more than 40 different ligands, well beyond the more limited scope of the LDL receptor. 1 LRP-1 ligands include proteases, such as tissuetype plasminogen activator (tPA) and matrix metalloprotease-9, growth factors, extracellular matrix proteins, and foreign toxins. LRP-1 also mediates the endocytosis of plasma membrane proteins, including the urokinase receptor (uPAR), amyloid precursor protein, and tissue factor. 4 By regulating cell-surface uPAR, LRP-1 controls the activity of cell signaling factors downstream of uPAR, including extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase and Rac1. 5,6 In mice, systemic LRP-1 gene deletion is embryonic lethal. 7 LRP-1 is synthesized as a 600-kDa single-chain precursor and processed by a furin-like protease into the mature 2-chain form. 8 The 85-kDa ␤-chain includes a small ectodomain, a single transmembrane domain, and the cytoplasmic tail. The 515-kDa ␣-chain is entirely extracellular but coupled to the ␤-chain through strong noncovalent forces. 8 The ␣-chain includes 4 clusters of cysteine-rich complementtype repeats (CRs). 1 The second and fourth clusters of CRs mediate most ligand-binding interactions, with the exception of the protease inhibitor, ␣ 2 M, which binds to the first and second CR clusters. 9 In addition to its role as a regulator of cell signaling downstream of uPAR, LRP-1 directly activates cell signaling upon binding of ligands, including tPA, activated ␣ 2 M, and apolipoprotein E. [10][11][12] The exact mechanism by which ligand binding to LRP-1 initiates cell signaling is unclear; however, the LRP-1 ␤-chain contains 2 NPxY motifs, the more C-terminal of which binds signaling adaptor proteins, such as Shc, c-Jun amino-terminal kinase (JNK)-interacting protein-1/2 (JIP-1/JIP-2), Dab-1, and FE65. [13][14][15] Adaptor protein binding to the LRP-1 ␤-chain is controlled by tyrosine phosphorylation, which occurs in response to ligand binding or the activity of nonreceptor tyrosine kinases. 11,13,16 LRP-1-JIP complex sequesters JNK and thereby prev...

Low Density Lipoprotein Receptor-related Protein (LRP1) Regulates Rac1 and RhoA Reciprocally to Control Schwann Cell Adhesion and Migration

“…In addition to the direct pathway, under study here, in which LRP1 ligands activate cell signaling, LRP1 also indirectly regulates cell signaling by controlling the cell surface abundance of other receptors, such as uPAR (29,48) and TNF receptor-1 (49). Direct and indirect pathways may provide opposing signals.…”

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

“…Although LRP1 was originally described as a scavenger receptor for extracellular proteins (9), it is now clear that LRP1 function is more complex than just mediating endocytosis (9). LRP1 can regulate cell signaling events and functions in inflammation and neurogenesis (12,44).…”

“…Upon binding to LRP1 on the cell surface, LRP1 ligands are internalized, dissociate in acidified endosomes, and are delivered to lysosomes, whereas LRP1 is recycled to the cell surface (10). LRP1 also mediates endocytosis of cell surface receptors (11) and, in this manner, participates in the regulation of cell signaling events (12,13).…”

RBBP9: A tumor-associated serine hydrolase activity required for pancreatic neoplasia

“…Two previously characterized serine hydrolases, seprase/FAP and complement C1r, were the only other enzymes to display similar activity profiles in the resected clinical specimens. Seprase is frequently overexpressed in carcinomaassociated fibroblasts and has reported roles in tumorigenesis, metastasis, extracellular matrix degradation, and chemoresistance (15)(16)(17)(18), whereas C1r is an established factor in inflammation (19). As such, either of these enzymes could play key roles in pancreatic cancer.…”