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Science 301 (5638): 1394-1397

Copyright © 2003 by the American Association for the Advancement of Science

ß-Arrestin 2 Mediates Endocytosis of Type III TGF-ß Receptor and Down-Regulation of Its Signaling

Wei Chen,1 Kellye C. Kirkbride,2 Tam How,2 Christopher D. Nelson,1 Jinyao Mo,2 Joshua P. Frederick,3 Xiao-Fan Wang,3 Robert J. Lefkowitz,1* Gerard C. Blobe2

Abstract: ß-Arrestins bind to activated seven transmembrane–spanning (7TMS) receptors (G protein–coupled receptors) after the receptors are phosphorylated by G protein–coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of ß-arrestin 2 (ßarr2) for the single transmembrane–spanning type III transforming growth factor–ß (TGF-ß) receptor (TßRIII, also referred to as betaglycan). Binding of ßarr2 to TßRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-ß receptor (TßRII), which is itself a kinase, rather than by a GRK. Association with ßarr2 led to internalization of both receptors and down-regulation of TGF-ß signaling. Thus, the regulatory actions of ß-arrestins are broader than previously appreciated, extending to the TGF-ß receptor family as well.

1 Howard Hughes Medical Institute, Duke University Medical Center, Departments of Medicine and Biochemistry, Durham, NC 27710, USA.
2 Duke University Medical Center, Departments of Medicine and Pharmacology and Cancer Biology, Durham, NC 27710, USA.
3 Duke University Medical Center, Department of Pharmacology and Cancer Biology, Durham, NC 27710, USA.

* To whom correspondence should be addressed. E-mail: lefko001{at}receptor-biol.duke.edu

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