Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling.
Intracellular trafficking of Notch and Notch ligands modulates signaling, suggesting that choreography of ligand and receptor translocation is essential for optimal Notch activity. Indeed, a major model for Notch signaling posits that Notch trans-endocytosis into the ligand-expressing (signal sending) cell is a key driving force for Notch signal transduction. The extracellular protein thrombospondin-2 (TSP2) enhances Notch signaling and binds to both Jagged1 and Notch3 ectodomains, potentially bridging two essential extracellular components of Notch signaling. We investigated the role of low density lipoprotein receptor-related protein-1 (LRP1), a TSP2 receptor, in the regulation of Notch3 signaling. TSP2 potentiation of Notch is blocked by the receptor-associated protein (an inhibitor of low density lipoprotein receptor-related protein function) and requires LRP1 expression in the signal-sending cell. TSP2 stimulates Notch3 endocytosis into wild type fibroblasts but not LRP1-deficient fibroblasts. Finally, recombinant Notch3 and Jagged1 interact with the LRP1 85-kDa B-chain, a subunit that lacks known ligand binding function. Our data suggest that LRP1 and TSP2 stimulate Notch activity by driving trans-endocytosis of the Notch ectodomain into the signal-sending cell and demonstrate a novel, non-cell autonomous function of LRP1 in cell-cell signaling.
Meng
He
H
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5622, USA.
Zhang
Xiaojie
X
Lee
Soo Jung
SJ
Strickland
Dudley K
DK
Lawrence
Daniel A
DA
Wang
Michael M
MM
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004705:Endocytosis; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017434:Protein Structure, Tertiary; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D019699:Thrombospondins / Q000378:metabolism*; D000099262:Thrombospondin 2
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D019699:Thrombospondins; D000099262:Thrombospondin 2; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C499374:NOTCH3 protein, human
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