A p120 Catenin Isoform Switch Affects Rho Activity, Induces Tumor Cell Invasion, and Predicts Metastatic Disease*
- Masahiro Yanagisawa‡,
- Deborah Huveldt‡,
- Pamela Kreinest‡,
- Christine M. Lohse§,
- John C. Cheville¶,
- Alexander S. Parker∥,
- John A. Copland‡ and
- Panos Z. Anastasiadis‡1
- Departments of ‡Cancer Biology and ∥Urology, Mayo Clinic, Jacksonville, Florida 32224 and the Departments of §Health Sciences Research and ¶Anatomic Pathology, Mayo Clinic, Rochester, Minnesota 55095
- 1 To whom correspondence should be addressed: Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Bldg., Rm. 307, 4500 San Pablo Rd., Jacksonville, FL 32224. Fax: 904-953-0277; E-mail: panos{at}mayo.edu.
Abstract
p120 catenin is a cadherin-associated protein that regulates Rho GTPases and promotes the invasiveness of E-cadherin-deficient cancer cells. Multiple p120 isoforms are expressed in cells via alternative splicing, and all of them are essential for HGF signaling to Rac1. However, only full-length p120 (isoform 1) promotes invasiveness. This selective ability of p120 isoform 1 is mediated by reduced RhoA activity, both under basal conditions and following HGF treatment. All p120 isoforms can bind RhoA in vitro, via a central RhoA binding site. However, only the cooperative binding of RhoA to the central p120 domain and to the alternatively spliced p120 N terminus stabilizes RhoA binding and inhibits RhoA activity. Consistent with this, increased expression of p120 isoform 1, when compared with other p120 isoforms, is predictive of renal tumor micrometastasis and systemic progression, following nephrectomy. Furthermore, ectopic expression of the RhoA-binding, N-terminal domain of p120 is sufficient to block the ability of p120 isoform 1 to inhibit RhoA and to promote invasiveness. The data indicate that the increased expression of p120 isoform 1 during tumor progression contributes to the invasive phenotype of cadherin-deficient carcinomas and that the N-terminal domain of p120 is a valid therapeutic target.
Footnotes
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↵2 The abbreviations used are: EMT, epithelial to mesenchymal transition; HGF, hepatocyte growth factor; ccRCC, clear cell renal cell carcinoma; shRNA, short hairpin RNA; mAb, monoclonal antibody; ANOVA, analysis of variance; GEF, guanine nucleotide exchange factor; PBS, phosphate-buffered saline; GST, glutathione S-transferase; ROCK, RhoA-Rho kinase.
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↵* This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA100467 (to P. A.) and R01CA104505 (to J. A. C.). This work was also supported by a Team Science Program grant from the James and Esther King Biomedical Research Program of the Florida Department of Health (to P. Z. A. and J. A. C.). 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.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.
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- Received February 13, 2008.
- Revision received April 9, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
