Endocytosis of G Protein-Coupled Receptors Is Regulated by Clathrin Light Chain Phosphorylation
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- 作者：Filipe Ferreira ; Matthew Foley ; Alex Cooke ; Margaret Cunningham ; Gemma Smith ; Robert Woolley ; Graeme Henderson ; Eamonn Kelly ; Stuart Mundell ; Elizabeth Smythe
- 刊名：Current Biology
- 出版年：2012
- 出版时间：7 August, 2012
- 年：2012
- 卷：22
- 期：15
- 页码：1361-1370
- 全文大小：870 K
文摘
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Summary
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.