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MBC in Press, published online ahead of print July 26, 2006
Mol. Biol. Cell 10.1091/mbc.E06-05-0421

A more recent version of this article appeared on October 1, 2006
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Submitted on May 16, 2006
Revised on July 18, 2006
Accepted on July 19, 2006

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

Peter A. Keyel,* Sanjay K. Mishra,* Robyn Roth,{dagger} John E. Heuser,{dagger} Simon C. Watkins,* and Linton M. Traub*

*Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; {dagger}Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110

Monitoring Editor: Sandra Schmid

Sorting of transmembrane cargo into clathrin-coated vesicles requires endocytic adaptors, yet 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.

Address correspondence to: Linton M. Traub (traub{at}pitt.edu)




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