TY - JOUR
T1 - Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β
AU - Hart, Matthew J.
AU - De Los Santos, Rico
AU - Albert, Iris N.
AU - Rubinfeld, Bonnee
AU - Polakis, Paul
N1 - Funding Information:
We thank Tuyen Vuong and Jaina Sumortin for assistance with plasmid preparations and nucleotide sequencing, and David Lowe and Barbara Belisle for production of baculovirus and Sf9 cells. This work was supported in part by an SBIR grant number 1R43CA69931 from the National Institutes of Health.
PY - 1998/5/7
Y1 - 1998/5/7
N2 - Background: Inactivation of the adenomatous polyposis coli (APC) tumor suppressor protein is responsible for both inherited and sporadic forms of colon cancer. Growth control by APC may relate to its ability to downregulate β-catenin post-translationally. In cancer, mutations in APC ablate its ability to regulate β-catenin, and mutations in β-catenin prevent its downregulation by wild-type APC. Moreover, signaling by the protein product of the wnt-1 proto-oncogene upregulates β-catenin and promotes tumorigenesis in mice. In a Xenopus developmental system, Wnt-1 signaling was inhibited by Axin, the product of the murine fused gene. This suggests a possible link between Axin, the Wnt-1 signaling components β-catenin and glycogen synthase kinase 3β (GSK3β), and APC. Results: Human Axin (hAxin) binds directly to β-catenin, GSK3β, and APC in vitro, and the endogenous proteins are found in a complex in cells. Binding sites for Axin were mapped to a region of APC that is typically deleted due to cancer-associated mutations in the APC gene. Overexpression of hAxin strongly promoted the downregulation of wild-type β-catenin in colon cancer cells, whereas mutant oncogenic β-catenin was unaffected. The downregulation was increased by deletion of the APC-binding domain from Axin, suggesting that APC may function to derepress Axin activity. In addition, hAxin dramatically facilitated the phosphorylation of APC and β-catenin by GSK3β in vitro. Conclusions: Axin acts as a scaffold upon which APC, β-catenin and GSK3β assemble to coordinate the regulation of β-catenin signaling.
AB - Background: Inactivation of the adenomatous polyposis coli (APC) tumor suppressor protein is responsible for both inherited and sporadic forms of colon cancer. Growth control by APC may relate to its ability to downregulate β-catenin post-translationally. In cancer, mutations in APC ablate its ability to regulate β-catenin, and mutations in β-catenin prevent its downregulation by wild-type APC. Moreover, signaling by the protein product of the wnt-1 proto-oncogene upregulates β-catenin and promotes tumorigenesis in mice. In a Xenopus developmental system, Wnt-1 signaling was inhibited by Axin, the product of the murine fused gene. This suggests a possible link between Axin, the Wnt-1 signaling components β-catenin and glycogen synthase kinase 3β (GSK3β), and APC. Results: Human Axin (hAxin) binds directly to β-catenin, GSK3β, and APC in vitro, and the endogenous proteins are found in a complex in cells. Binding sites for Axin were mapped to a region of APC that is typically deleted due to cancer-associated mutations in the APC gene. Overexpression of hAxin strongly promoted the downregulation of wild-type β-catenin in colon cancer cells, whereas mutant oncogenic β-catenin was unaffected. The downregulation was increased by deletion of the APC-binding domain from Axin, suggesting that APC may function to derepress Axin activity. In addition, hAxin dramatically facilitated the phosphorylation of APC and β-catenin by GSK3β in vitro. Conclusions: Axin acts as a scaffold upon which APC, β-catenin and GSK3β assemble to coordinate the regulation of β-catenin signaling.
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U2 - 10.1016/s0960-9822(98)70226-x
DO - 10.1016/s0960-9822(98)70226-x
M3 - Article
C2 - 9601641
AN - SCOPUS:0032492954
VL - 8
SP - 573
EP - 581
JO - Current Biology
JF - Current Biology
SN - 0960-9822
IS - 10
ER -