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J. Biol. Chem., Vol. 278, Issue 34, 31781-31789, August 22, 2003

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Functional Correlates of Mutations in -Catenin Exon 3 Phosphorylation Sites^*

Elayne Provost , Yumi Yamamoto , Isabel Lizardi , Jessica Stern , Thomas G. D'Aquila , Richard B. Gaynor  and David L. Rimm  ¶

From the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023 and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390

-Catenin-mediated signaling can be constitutively activated by truncation or mutation of serine and threonine residues in exon 3. Mutations in this region are observed in many human tumors. Examination of the locations of these mutations reveals interesting patterns; specifically, Ser⁴⁵ and Thr⁴¹ appear more frequently in malignant tumors, and Ser³⁷ and Ser³³ are more common in benign entities. To test whether these patterns represent functional differences in -catenin signaling mechanisms, we generated mutations of each of these residues. Stable transformation of Madin-Darby canine kidney cells showed a transformed phenotype with each of the four mutations, as assessed by growth in soft agar and collagen. Functional assays including proliferation assays, cell shedding assays, and wounding assays demonstrated two groups. Ser⁴⁵ and Thr⁴¹ represent a more transformed phenotype, whereas Ser³⁷ and Ser³³ behaved similarly to the vector in these assays. Assessment of downstream genes demonstrated increased activation of the -catenin target gene cyclin D1 by Ser⁴⁵. Finally, we examined the kinase activity of IB kinase- and found that this kinase, unlike glycogen synthase kinase-3, appears to preferentially phosphorylate Ser⁴⁵ and Thr⁴¹, independent of priming by casein kinase-1. We conclude that these sites may represent an alternative (non-wnt) signaling pathway, which may be inappropriately activated in tumors with mutations of these residues.

Received for publication, May 12, 2003 , and in revised form, June 5, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a grant from the Patrick and Catherine Weldon Donaghue Foundation for Medical Research and by grants from the National Institutes of Health, including RO-1 GM 57604. To whom correspondence should be addressed: Dept. of Pathology, Yale University School of Medicine, P. O. Box 208023, 310 Cedar St., New Haven, CT 06520-8023. Tel.: 203-737-4204; Fax: 203-737-5089; E-mail: david.rimm{at}yale.edu.

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