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A more recent version of this article appeared on November 1, 2002
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Submitted on July 10, 2002
Accepted on August 16, 2002
1 Department of Biochemistry and Molecular Biology and Thoracic Diseases Research Unit, Mayo Clinic, Rochester MN 55905
2 Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
* Corresponding author. E-mail address: leof.edward{at}mayo.edu.
Transforming growth factor ß (TGF-ß) superfamily members regulate a wide range of biological processes by binding to two transmembrane serine/threonine kinase receptors, type I and type II. We have previously shown that the internalization of these receptors is inhibited by K+ depletion, cytosol acidification or hypertonic medium, suggesting the involvement of clathrin coated pits. However, the involvement of the clathrin-associated adaptor complex AP2 and the identity of the AP2 subunit that binds the receptors were not known. Here we have studied these issues by combining studies on intact cells with in vitro assays. Using fluorescence photobleaching recovery to measure the lateral mobility of the receptors on live cells (untreated or treated to alter their coated pit structure), we demonstrated that their mobility is restricted by interactions with coated pits. These interactions were transient, and mediated through the receptors' cytoplasmic tails. To measure direct binding of the receptors to specific AP2 subunits, we employed yeast two-hybrid screens and in vitro biochemical assays. In contrast to most other plasma membrane receptors which bind to AP2 via the µ2 subunit, AP2/TGF-ß receptor binding was mediated by a direct interaction between the ß2-adaptin N-terminal trunk domain and the cytoplasmic tails of the receptors; no binding was observed to the µ2, 
, or 
2 subunits of AP2 or to µ1 of AP1. The data uniquely demonstrate both in vivo and in vitro the ability of ß2-adaptin to directly couple TGF-ß receptors to AP2 and to clathrin-coated pits, providing the first in vivo evidence for interactions of a transmembrane receptor with ß2-adaptin.
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