J. Cell Biol., Volume 145, Number 4, May 17, 1999 741-756

Domains of Axin Involved in Protein-Protein Interactions, Wnt Pathway Inhibition, and Intracellular Localization

François Fagotto,^* Eek-hoon Jho, Li Zeng, Thomas Kurth,^* Thomas Joos,^* Christine Kaufmann,^* and Frank Costantini

^* Division of Cell Biology, Max-Planck Institute for Developmental Biology, 72076 Tübingen, Germany; and  Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York 10032

Axin was identified as a regulator of embryonic axis induction in vertebrates that inhibits the Wnt signal transduction pathway. Epistasis experiments in frog embryos indicated that Axin functioned downstream of glycogen synthase kinase 3 (GSK3) and upstream of -catenin, and subsequent studies showed that Axin is part of a complex including these two proteins and adenomatous polyposis coli (APC). Here, we examine the role of different Axin domains in the effects on axis formation and -catenin levels. We find that the regulators of G-protein signaling domain (major APC-binding site) and GSK3-binding site are required, whereas the COOH-terminal sequences, including a protein phosphatase 2A binding site and the DIX domain, are not essential. Some forms of Axin lacking the -catenin binding site can still interact indirectly with -catenin and regulate -catenin levels and axis formation. Thus in normal embryonic cells, interaction with APC and GSK3 is critical for the ability of Axin to regulate signaling via -catenin. Myc-tagged Axin is localized in a characteristic pattern of intracellular spots as well as at the plasma membrane. NH₂-terminal sequences were required for targeting to either of these sites, whereas COOH-terminal sequences increased localization at the spots. Coexpression of hemagglutinin-tagged Dishevelled (Dsh) revealed strong colocalization with Axin, suggesting that Dsh can interact with the Axin/APC/GSK3/-catenin complex, and may thus modulate its activity.

-catenin;  glycogen synthase kinase 3 (GSK3);  adenomatous polyposis coli (APC);  Dishevelled (Dsh);  dorsal axis formation

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