Phosphorylation and Free Pool of β-Catenin Are Regulated by Tyrosine Kinases and Tyrosine Phosphatases during Epithelial Cell Migration*
- From the ‡Department of Molecular Biology, Max Planck Institute for Biochemistry, Am Klopferspitz 18a, 82152 Martinsried, Federal Republic of Germany and ¶Swiss Institute for Experimental Cancer Research (ISREC), Chemin des Boveresses 155, 1066 Epalinges, Switzerland
Abstract
Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. Although the integrity of cell-cell contacts, such as adherens junctions, is essential for the maintenance of functional epithelia, they need to be rapidly disassembled during migration. The transmembrane cell adhesion protein E-cadherin and the cytoplasmic catenins are molecular elements of these structures. Here we demonstrate that epithelial cell migration is accompanied by tyrosine phosphorylation of β-catenin and an increase of its free cytoplasmic pool. We show further that the protein-tyrosine phosphatase LAR (leukocyte common antigen related) colocalizes with the cadherin-catenin complex in epithelial cells and associates with β-catenin and plakoglobin. Interestingly, ectopic expression of protein-tyrosine phosphatase (PTP) LAR inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of β-catenin; moreover, it inhibits tumor formation in nude mice. These data support a function for PTP LAR in the regulation of epithelial cell-cell contacts at adherens junctions as well as in the control of β-catenin signaling functions. Thus PTP-LAR appears to play an important role in the maintenance of epithelial integrity, and a loss of its regulatory function may contribute to malignant progression and metastasis.
Footnotes
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↵* This work was supported by a grant from Sugen, Inc.The costs of publication of this article were defrayed in part by the payment of page charges. The 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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↵§ To whom correspondence should be addressed: ARIAD Pharmaceuticals, Inc., Cell Biology and Genetics, 26 Landsdowne St., Cambridge, MA 02139. Tel.: 617-494-0400; Fax: 617-252-0851. E-mail:Thomas.Mueller{at}ariad.com.
- Abbreviations:
- EMT
-
epithelial-mesenchymal transition
- PTP
-
protein-tyrosine phosphatase
- hPTP
-
human PTP
- TK
-
tyrosine kinase
- APC
-
adenomatous polyposis coli
- LEF1
-
lymphoid enhancer factor 1
- EGF
-
epidermal growth factor
- PCR
-
polymerase chain reaction
- PAGE
-
polyacrylamide gel electrophoresis
- GST
-
glutathione S-transferase
- PBS
-
phosphate-buffered saline
- LAR
-
leukocyte common antigen related
-
- Received October 22, 1998.
- Revision received January 4, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
