Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes.
The Wnt-1 proto-oncogene induces the accumulation of beta-catenin and plakoglobin, two related proteins that associate with and functionally modulate the cadherin cell adhesion proteins. Here we have investigated the effects of Wnt-1 expression on the tumor suppressor protein APC, which also associates with catenins. Expression of Wnt-1 in two different cell lines greatly increased the stability of APC-catenin complexes. The steady-state levels of both catenins and APC were elevated by Wnt-1, and the half-lives of both beta-catenin and plakoglobin associated with APC were also markedly increased. The stabilization of catenins by Wnt-1 was primarily the result of a selective increase in the amount of uncomplexed, monomeric beta-catenin and plakoglobin, detected both by affinity precipitation and size-exclusion chromatography of cell extracts. Exogenous expression of beta-catenin was possible in cells already responding to Wnt-1 but not in the parental cells, suggesting that Wnt-1 inhibits an essential regulatory mechanism for beta-catenin turnover. APC has the capacity to oppose this Wnt-1 effect in experiments in which overexpression of the central region of APC significantly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1. Thus, the Wnt-1 signal transduction pathway leads to the accumulation of monomeric catenins and stabilization of catenin complex formation with both APC and cadherins.
Papkoff
J
J
SUGEN, Inc., Redwood City, California 94063, USA.
Rubinfeld
B
B
Schryver
B
B
Polakis
P
P
D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000302:isolation & purification / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000302:isolation & purification / Q000378:metabolism*; D051180:Desmoplakins; D004591:Electrophoresis, Polyacrylamide Gel; D015870:Gene Expression; D017491:Genes, APC; D008954:Models, Biological; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015534:Trans-Activators; D014162:Transfection; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin; D051185:gamma Catenin
D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin; D051185:gamma Catenin; D011505:Protein-Tyrosine Kinases