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Molecular and Cellular Biology, September 2002, p. 6393-6405, Vol. 22, No. 18
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.18.6393-6405.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

I-mfa Domain Proteins Interact with Axin and Affect Its Regulation of the Wnt and c-Jun N-Terminal Kinase Signaling Pathways

Shuichi Kusano and Nancy Raab-Traub*

Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7295

Received 29 April 2002/ Returned for modification 23 May 2002/ Accepted 12 June 2002

I-mfa has been identified as an inhibitor of myogenic basic helix-loop-helix transcription factors, and a related human I-mfa domain-containing protein (HIC) also has been identified as a protein that regulates Tat- and Tax-mediated expression of viral promoters. HIC and I-mfa represent a family of proteins that share a highly conserved cysteine-rich domain, termed the I-mfa domain. We show here that both I-mfa domain proteins, HIC and I-mfa, interacted in vivo with the Axin complex through their C-terminal I-mfa domains. This interaction inhibited Axin-mediated downregulation of free levels of cytosolic ß-catenin. I-mfa and HIC also both directly interacted with lymphocyte enhancer factor (LEF); however, I-mfa but not HIC significantly inhibited reporter constructs regulated by ß-catenin. The overexpression of HIC but not I-mfa decreased the inhibitory effects of Axin on ß-catenin-regulated reporter constructs, while both HIC and I-mfa decreased Axin-mediated c-Jun N-terminal kinase (JNK) activation. These data reveal for the first time that I-mfa domain proteins interact with the Axin complex and affect Axin regulation of both the Wnt and the JNK activation pathways. Interestingly, HIC differs from I-mfa in that I-mfa affects both Axin function and T-cell factor- or LEF-regulated transcription in the Wnt signaling pathway while HIC affects primarily Axin function.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, CB#7295, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7295. Phone: (919) 966-1701. Fax: (919) 966-9673. E-mail: nrt{at}med.unc.edu.

Molecular and Cellular Biology, September 2002, p. 6393-6405, Vol. 22, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.18.6393-6405.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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