Notch Ligand Endocytosis Generates Mechanical Pulling Force Dependent on Dynamin, Epsins, and Actin

被引:174
作者
Meloty-Kapella, Laurence [4 ]
Shergill, Bhupinder [1 ]
Kuon, Jane [4 ]
Botvinick, Elliot [1 ,2 ,3 ]
Weinmaster, Gerry [4 ,5 ,6 ]
机构
[1] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92612 USA
[2] Univ Calif Irvine, Beckman Laser Inst, Irvine, CA 92612 USA
[3] Univ Calif Irvine, Edwards Lifesci Ctr Adv Cardiovasc Technol, Irvine, CA 92612 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA
[5] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
[6] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
关键词
CLATHRIN-MEDIATED ENDOCYTOSIS; MIND BOMB; LIGHT-CHAINS; ENTH DOMAIN; DROSOPHILA; PROTEIN; DELTA; RECEPTOR; PATHWAY; TRAFFICKING;
D O I
10.1016/j.devcel.2012.04.005
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Notch signaling induced by cell surface ligands is critical to development and maintenance of many eukaryotic organisms. Notch and its ligands are integral membrane proteins that facilitate direct cell-cell interactions to activate Notch proteolysis and release the intracellular domain that directs Notch-specific cellular responses. Genetic studies suggest that Notch ligands require endocytosis, ubiquitylation, and epsin endocytic adaptors to activate signaling, but the exact role of ligand endocytosis remains unresolved. Here we characterize a molecularly distinct mode of clathrin-mediated endocytosis requiring ligand ubiquitylation, epsins, and actin for ligand cells to activate signaling in Notch cells. Using a cell-bead optical tweezers system, we obtained evidence for cell-mediated mechanical force dependent on this distinct mode of ligand endocytosis. We propose that the mechanical pulling force produced by endocytosis of Notch-bound ligand drives conformational changes in Notch that permit activating proteolysis.
引用
收藏
页码:1299 / 1312
页数:14
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