期刊
CURRENT BIOLOGY
卷 22, 期 15, 页码 1361-1370出版社
CELL PRESS
DOI: 10.1016/j.cub.2012.05.034
关键词
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资金
- MRC [G0300452]
- BBSRC
- FCT
- POPH/FSE
- British Pharmacological Society
- University of Sheffield Light Microscopy Facility [GR077544AIA]
- MRC [G0300452, G0600943] Funding Source: UKRI
- British Heart Foundation [FS/11/49/28751, PG/09/091/28074] Funding Source: researchfish
- Medical Research Council [G0300452, G0600943] Funding Source: researchfish
Background: Signaling by transmembrane receptors such as G protein-coupled receptors (GPCRs) occurs at the cell surface and throughout the endocytic pathway, and signaling from the cell surface may differ in magnitude and downstream output from intracellular signaling. As a result, the rate at which signaling molecules traverse the endocytic pathway makes a significant contribution to downstream output. Modulation of the core endocytic machinery facilitates differential uptake of individual cargoes. Clathrin-coated pits are a major entry portal where assembled clathrin forms a lattice around invaginating buds that have captured endocytic cargo. Clathrin assembles into triskelia composed of three clathrin heavy chains and associated clathrin light chains (CLCs). Despite the identification of clathrin-coated pits at the cell surface over 30 years ago, the functions of CLCs in endocytosis have been elusive. Results: In this work, we identify a novel role for CLCs in the regulated endocytosis of specific cargoes. Small interfering RNA-mediated knockdown of either CLCa or CLCb inhibits the uptake of GPCRs. Moreover, we demonstrate that phosphorylation of Ser204 in CLCb is required for efficient endocytosis of a subset of GPCRs and identify G protein-coupled receptor kinase 2 (GRK2) as a kinase that can phosphorylate CLCb on Ser204. Overexpression of CLCbS204A specifically inhibits the endocytosis of those GPCRs whose endocytosis is GRK2-dependent. Conclusions: Together, these results indicate that CLCb phosphorylation acts as a discriminator for the endocytosis of specific GPCRs.
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