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Regulation of MAPK/JNK signaling pathway and TGF-beta signaling pathway by axin

Authors Rui, Hongliang
Issue Date 2004
Summary Axin was originally identified from the characterization of the Fused locus, the disruption of which leads to duplication of axis and embryonic lethality. Axin is a multidomain protein that interacts with multiple proteins and functions as a negative regulator of Wnt signaling by downregulating the β-catenin levels. It also plays an important role in a JNK signaling pathway. Through study functions of Axin C-terminal, we found Axin interacts with three SUMO-1 (s̲mall u̲biquitin-related m̲o̲difier) E3 ligases, PIAS1, PIASxβ, and PIASy. The extreme C-terminal six amino acid residues of Axin are critical for the Axin/E3 interaction. In consistence with the presence of a doublet of the “KVE/D” sumoylation consensus motif at the C-terminal end (KVEKVD), we found that Axin is heavily sumoylated. Deletion of the C-terminal six amino acid drastically reduced sumoylation, indicating that the C-terminal six amino acid stretch is the main sumoylation site for Axin. In addition, Axin lacking last six residues, Axin∆C6, failed to activate JNK although it was intact in both its interaction with MEKK1and homodimerization. Axin∆C6 still could effectively destabilize β-catenin and attenuate LEF1 transcriptional activity. Taken together, we demonstrate that sumoylation plays a role for Axin to function in the JNK pathway. We also identified Arkadia as novel Axin interacting protein. Arkadia is a protein that enhances signaling activity of TGF-β/Nodal and BMP through interacting with inhibitory Smad, Smad7, and function as an E3 ubiquitin ligase to introduce poly-ubiquitination of Smad7. We showed that both Axin and Arkadia can activate TGF-β dependent transcription, and the certain effect of Axin is mainly through Arkadia. Moreover, Axin interacts with inhibitory Smad, Smad7. Axin is able to enhance poly-ubiquitination of Smad7, which also requires Arkadia. Our finding suggests Axin may serve as an adaptor, facilitating Arkadia mediated poly-ubiquitination of Smad7.
Note Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004
Language English
Format Thesis
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