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Regulation of S33/S37 phosphorylated ß-catenin in normal and transformed cells

Einat Sadot^1,*, Maralice Conacci-Sorrell¹, Jacob Zhurinsky¹, Dalia Shnizer², Zeev Lando², Dorit Zharhary², Zvi Kam¹, Avri Ben-Ze'ev¹ and Benjamin Geiger^1,

¹ Department of Molecular Cell Biology, Weizmann Institute of Science Rehovot 76100 Israel
² Sigma Aldrich Israel, Park Rabin, Rehovot 76100, Israel
^* Present address: The Department of Ornamental Horticulture, The Volcani Center, Beit-Dagan, P.O.B. 6, 50250 Israel

Author for correspondence (e-mail: benny.geiger{at}weizmann.ac.il )

Accepted 23 April 2002

A novel phosphorylation-specific antibody (pß-catenin) was generated against a peptide corresponding to amino acids 33-45 of human ß-catenin, which contained phosphorylated serines at positions 33 and 37. This antibody is specific to phosphorylated ß-catenin and reacts neither with the non-phosphorylated protein nor with phosphorylated or non-phosphorylated plakoglobin. It weakly interacts with S33Y ß-catenin but not with the S37A mutant. pß-catenin is hardly detectable in normal cultured cells and accumulates (up to 55% of total ß-catenin) upon overexpression of the protein or after blocking its degradation by the proteasome. Inhibition of both GSK-3ß and the proteasome resulted in a rapid (t_1/2=10 minutes) and reversible reduction in pß-catenin levels, suggesting that the protein can undergo dephosphorylation in live cells, at a rate comparable to its phosphorylation by GSK-3ß. pß-catenin interacts with LEF-1, but fails to form a ternary complex with DNA, suggesting that it is transcriptionally inactive. Immunofluorescence microscopy indicated that pß-catenin accumulates in the nuclei of MDCK and BCAP cells when overexpressed and is transiently associated with adherens junctions shortly after their formation. pß-catenin only weakly interacts with co-transfected N-cadherin, although it forms a complex with the ubiquitin ligase component ß-TrCP. SW480 colon cancer cells that express a truncated APC, at position 1338, contain high levels of pß-catenin, whereas HT29 cells, expressing APC truncated at position 1555, accumulate non-phosphorylated ß-catenin, suggesting that the 1338-1555 amino acid region of APC is involved in the differential regulation of the dephosphorylation and degradation of pß-catenin.

Key words: ß-catenin, GSK-3ß, APC

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