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Modulation of α-catenin Tyr phosphorylation by SHP2 positively effects cell transformation induced by the constitutively active FGFR3

Oncogene volume 25, pages 7166–7179 (2006)Cite this article

Abstract

The Src homology 2 phosphotyrosyl phosphatase (SHP2) is a nonreceptor-type phosphatase that acts as a positive transducer of receptor Tyr kinase (RTK) signaling, particularly the Ras-REK and PI3K-Akt pathways. Recently, we have demonstrated that SHP2 is required for cell transformation induced by the constitutively active fibroblast growth factor receptor 3 (K/E-FR3) (Oncogene, 22, 6909–6918). In that study, we had detected a phosphotyrosyl protein of ∼100 KDa (p100) in cells expressing dominant-negative SHP2 (R/E-SHP2), but its identity and relevance in SHP2-meditaed transformation was not known. Here, we report the identification of p100 as α-catenin, a vinculin-related protein involved in adherens junction-mediated intercellular adhesion. We show that α-catenin becomes Tyr phosphorylated in intercellular adhesion-dependent manner and this event is counteracted by SHP2. Substrate trapping in intact cells and immunocomplex phosphatse assays confirmed that α-catenin is in deed an SHP2 substrate. Tyr phosphorylation of α-catenin enhances its translocation to the plasma membrane and its interaction with β-catenin, leading to enhanced actin polymerization and stabilization of adherens junction-mediated intercellular adhesion, a phenomenon commensurate with loss of the transformation phenotype. Site-directed mutagenesis studies also suggested that Tyr phosphorylation of α-catenin enhances its inhibitory role on cell transformation. Based on our previous work and the current report, we demonstrate that mediation of cell transformation by SHP2 is a complex process that involves modulation of the Ras-ERK and PI3K-Akt signaling pathways, intercellular adhesion, focal adhesion and actin cytoskeletal reorganization. To our knowledge, this is the first report showing regulation of α-catenin function by Tyr phosphorylation and its inhibitory effect on cell transformation.

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Acknowledgements

We thank Dr Fred Minnear (West Virginia University) for providing us with the α-catenin cDNA. We would also like to thank Karen hays for her technical assistance. This work was supported by startup funds from the West Virginia University and by the COBRE (NIH) Grant to YMA.

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  1. Department of Biochemistry and Molecular Pharmacology, Robert C Byrd Health Sciences Center, West Virginia University, Morgantown, WV, USA

    J Burks & Y M Agazie

  2. The Marry Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, USA

    J Burks & Y M Agazie

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Correspondence to Y M Agazie.

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Burks, J., Agazie, Y. Modulation of α-catenin Tyr phosphorylation by SHP2 positively effects cell transformation induced by the constitutively active FGFR3. Oncogene 25, 7166–7179 (2006). https://doi.org/10.1038/sj.onc.1209728

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