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Molecular and Cellular Biology, September 2007, p. 6183-6194, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00132-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Erbin Inhibits Transforming Growth Factor ß Signaling through a Novel Smad-Interacting Domain{triangledown}

Fangyan Dai,1,2,3 Chenbei Chang,4 Xia Lin,2,3 Penggao Dai,5 Lin Mei,5 and Xin-Hua Feng1,2,3*

Department of Molecular and Cellular Biology,1 Michael E. DeBakey Department of Surgery,2 The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030,3 Department of Cell Biology, University of Alabama, Birmingham, Alabama 35294,4 Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, and Department of Neurology, Medical College of Georgia, Augusta, Georgia 309125

Received 21 January 2007/ Returned for modification 22 March 2007/ Accepted 11 June 2007

Smad proteins are critical intracellular signaling mediators for the transforming growth factor ß (TGFß) superfamily. Here, we report that Erbin (for "ErbB2/Her2-interacting protein"), which contains leucine-rich repeats and a PDZ (PSD-95/DLG/ZO-1) domain, interacts specifically with Smad3 and, to a lesser extent, with Smad2 through a novel Smad-interacting domain (SID) adjacent to its PDZ domain. Increased expression of Erbin does not affect the level of TGFß-induced phosphorylation of Smad2/Smad3, but it physically sequesters Smad2/Smad3 from their association with Smad4 and hence negatively modulates TGFß-dependent transcriptional responses and cell growth inhibition. An isoform of Erbin encoded by an alternatively spliced transcript in human tissues lacks this SID and fails to inhibit TGFß responses. Consistently, knockdown of the endogenous Erbin gene with short hairpin RNA enhances TGFß-induced antiproliferative and transcriptional responses. In addition, Erbin suppresses activin/Smad2-dependent, but not BMP/Smad1-mediated, induction of endogenous gene expression in Xenopus embryos. Therefore, these results define Erbin as a novel negative modulator of Smad2/Smad3 functions and expand the physiological role of Erbin to the regulation of TGFß signaling.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room 137D, Houston, TX 77030. Phone: (713) 798-4756. Fax: (713) 798-4093. E-mail: xfeng{at}bcm.edu

{triangledown} Published ahead of print on 25 June 2007.

Molecular and Cellular Biology, September 2007, p. 6183-6194, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00132-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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