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Title: Regulation of MAPK/JNK signaling pathway and TGF-beta signaling pathway by axin
Authors: Rui, Hongliang
Issue Date: 2004
Abstract: 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.
Description: Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004
xiv, 151 leaves : ill. (some col.) ; 30 cm. + 1 CD ROM (4 3/4 in)
HKUST Call Number: Thesis BICH 2004 Rui
Appears in Collections:BICH Doctoral Theses

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