QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 1 November 2005
doi: 10.1242/jcs.02650

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.02650v1 118/22/5345    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maurer, M. E. Articles by Cooper, J. A. Search for Related Content PubMed PubMed Citation Articles by Maurer, M. E. Articles by Cooper, J. A.

Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein

Division of Basic Sciences and Molecular and Cellular Biology Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA

^* Author for correspondence (e-mail: jcooper{at}fhcrc.org)

Accepted 16 August 2005

Rapid endocytosis of lipoprotein receptors involves NPxY signals contained in their cytoplasmic tails. Several proteins, including ARH and Dab2, can bind these sequences, but their importance for endocytosis may vary in different cell types. The lipoprotein receptor megalin is expressed in the visceral endoderm (VE), a polarized epithelium that supplies maternal nutrients to the early mammalian embryo. Dab2 is also expressed in the VE, and is required for embryo growth and gastrulation. Here, we show that ARH is absent from the VE, and Dab2 is required for uptake of megalin, its co-receptor cubilin, and a cubilin ligand, transferrin, from the brush border of the VE into intracellular vesicles. By making isoform-specific knock-in mice, we show that the p96 splice form of Dab2, which binds endocytic proteins, can fully rescue endocytosis. The more abundant p67 isoform, which lacks some endocytic protein binding sites, only partly rescues endocytosis. Endocytosis of cubilin is also impaired in VE and in mid-gestation visceral yolk sac when p96 is absent. These studies suggest that Dab2 p96 mediates endocytosis of megalin in the VE. In addition, rescue of embryonic viability correlates with endocytosis, suggesting that endocytosis mediated by Dab2 is important for normal development.

Key words: Dab2, Megalin, Endocytosis, Visceral endoderm, Lipoprotein receptor traffic, Endocytic adaptor protein

Related articles in JCS:

A Dab2 hand in development

JCS 2005 118: 2102. [Full Text]  

This article has been cited by other articles:

				T. M. Chlon, D. A. Taffany, J. Welsh, and M. J. Rowling Retinoids Modulate Expression of the Endocytic Partners Megalin, Cubilin, and Disabled-2 and Uptake of Vitamin D-Binding Protein in Human Mammary Cells J. Nutr., July 1, 2008; 138(7): 1323 - 1328. [Abstract] [Full Text] [PDF]

				E. R. Eden, X.-M. Sun, D. D. Patel, and A. K. Soutar Adaptor protein Disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia Hum. Mol. Genet., November 15, 2007; 16(22): 2751 - 2759. [Abstract] [Full Text] [PDF]

				A. Holmes, A. Flett, D. Coudreuse, H. C. Korswagen, and J. Pettitt C. elegans Disabled is required for cell-type specific endocytosis and is essential in animals lacking the AP-3 adaptor complex J. Cell Sci., August 1, 2007; 120(15): 2741 - 2751. [Abstract] [Full Text] [PDF]

				D.-H. Yang, K. Q. Cai, I. H. Roland, E. R. Smith, and X.-X. Xu Disabled-2 Is an Epithelial Surface Positioning Gene J. Biol. Chem., April 27, 2007; 282(17): 13114 - 13122. [Abstract] [Full Text] [PDF]

				Y. Jossin, L. Gui, and A. M. Goffinet Processing of Reelin by Embryonic Neurons Is Important for Function in Tissue But Not in Dissociated Cultured Neurons J. Neurosci., April 18, 2007; 27(16): 4243 - 4252. [Abstract] [Full Text] [PDF]

				C.-L. Huang, J.-C. Cheng, A. Stern, J.-T. Hsieh, C.-H. Liao, and C.-P. Tseng Disabled-2 is a novel {alpha}IIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation J. Cell Sci., November 1, 2006; 119(21): 4420 - 4430. [Abstract] [Full Text] [PDF]

				M. E. Maurer and J. A. Cooper The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH J. Cell Sci., October 15, 2006; 119(20): 4235 - 4246. [Abstract] [Full Text] [PDF]

				P. A. Keyel, S. K. Mishra, R. Roth, J. E. Heuser, S. C. Watkins, and L. M. Traub A Single Common Portal for Clathrin-mediated Endocytosis of Distinct Cargo Governed by Cargo-selective Adaptors Mol. Biol. Cell, October 1, 2006; 17(10): 4300 - 4317. [Abstract] [Full Text] [PDF]