Cited by 134Cellular transport and secretionCholesterol and Lipid MetabolismCaveolin-1 and cellular processes

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A Single Common Portal for Clathrin-mediated Endocytosis of Distinct Cargo Governed by Cargo-selective Adaptors

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Keyel, Peter A., Mishra, Sanjay K., Roth, Robyn, Heuser, John E., Watkins, Simon C., Traub, Linton M.·2006·Molecular Biology of the Cell

DOI 10.1091/mbc.e06-05-0421

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Abstract

Sorting of transmembrane cargo into clathrin-coated vesicles requires endocytic adaptors, yet RNA interference (RNAi)-mediated gene silencing of the AP-2 adaptor complex only disrupts internalization of a subset of clathrin-dependent cargo. This suggests alternate clathrin-associated sorting proteins participate in cargo capture at the cell surface, and a provocative recent proposal is that discrete endocytic cargo are sorted into compositionally and functionally distinct clathrin coats. We show here that the FXNPXY-type internalization signal within cytosolic domain of the LDL receptor is recognized redundantly by two phosphotyrosine-binding domain proteins, Dab2 and ARH; diminishing both proteins by RNAi leads to conspicuous LDL receptor accumulation at the cell surface. AP-2–dependent uptake of transferrin ensues relatively normally in the absence of Dab2 and ARH, clearly revealing delegation of sorting operations at the bud site. AP-2, Dab2, ARH, transferrin, and LDL receptors are all present within the vast majority of clathrin structures at the surface, challenging the general existence of specialized clathrin coats for segregated internalization of constitutively internalized cargo. However, Dab2 expression is exceptionally low in hepatocytes, likely accounting for the pathological hypercholesterolemia that accompanies ARH loss.

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Authors: Keyel, P. A., Mishra, S. K., Roth, R., Heuser, J. E., Watkins, S. C., & Traub, L. M.
Affiliations: University of Pittsburgh (US)
Washington University in St. Louis (US)
ORCID: Keyel, Peter A.
Mishra, Sanjay K.
Roth, Robyn
Watkins, Simon C.
Traub, Linton M.
Venue: Molecular Biology of the Cell
Publisher: American Society for Cell Biology (ASCB)
Published: 2006-10
Volume: 17
Issue: 10
Pages: 4300-4317
ISSN: 1059-1524 (ISSN-L)
1939-4586
DOI: 10.1091/mbc.e06-05-0421
OpenAlex: W1970268623
Semantic Scholar: 354796a98c8bf83ff7cfbbb3a43519acb1b8febd
Cited by: 134
References: 106
Citations by year: 2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 10 · 2013: 15 · 2012: 15
FWCI: 3.75
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Molecular Biology of the Cell (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders: American Heart Association
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK053249)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords: clathrin-mediated endocytosis, AP-2, Dab2, ArH+, LDL receptor, transferrin uptake, phosphotyrosine binding domain, receptor sorting, hepatocytes, hypercholesterolemia, RNA interference
MeSH terms: Animals, Cells, Cultured, Clathrin, Coated Pits, Cell-Membrane, Endocytosis, Golgi Apparatus, HeLa Cells, Humans, Cholesterol, LDL, Receptors, LDL, Transfection, ras GTPase-Activating Proteins, Protein Transport, Clathrin-Coated Vesicles, Hepatocytes, Adaptor Protein Complex 2, RNA Interference, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Rats

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A Single Common Portal for Clathrin-mediated Endocytosis of Distinct Cargo Governed by Cargo-selective Adaptors

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