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Modulation of alpha-catenin Tyr phosphorylation by SHP2 positively effects cell transformation induced by the

J Burks1, Y M Agazie

  • 1Department of Biochemistry and Molecular Pharmacology, Robert C Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-9142, USA.

Oncogene
|June 13, 2006
PubMed

Insights

The Src homology 2 phosphotyrosyl phosphatase (SHP2) dephosphorylates alpha-catenin, a protein crucial for cell adhesion. This dephosphorylation inhibits cell transformation by stabilizing cell-cell junctions and actin organization.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Src homology 2 phosphotyrosyl phosphatase (SHP2) is a key transducer in receptor tyrosine kinase (RTK) signaling pathways, including Ras-ERK and PI3K-Akt.
  • SHP2 plays a critical role in cell transformation, as previously demonstrated in studies involving fibroblast growth factor receptor 3 (FGFR3).

Purpose of the Study:

  • To identify a ~100 KDa phosphotyrosyl protein (p100) detected in cells with dominant-negative SHP2.
  • To elucidate the role of p100 and its regulation by SHP2 in SHP2-mediated cell transformation.

Main Methods:

  • Protein identification using mass spectrometry and biochemical assays.
  • Substrate trapping in intact cells and immunocomplex phosphatase assays to confirm SHP2-alpha-catenin interaction.
  • Site-directed mutagenesis to investigate the functional impact of alpha-catenin phosphorylation.

Main Results:

  • The ~100 KDa phosphotyrosyl protein (p100) was identified as alpha-catenin, a component of adherens junctions.
  • Alpha-catenin undergoes tyrosine phosphorylation in an intercellular adhesion-dependent manner, and this phosphorylation is counteracted by SHP2.
  • Tyrosine phosphorylation of alpha-catenin promotes its plasma membrane translocation, enhances interaction with beta-catenin, stabilizes adherens junctions, and inhibits cell transformation.

Conclusions:

  • Alpha-catenin is a novel substrate of SHP2, and its tyrosine phosphorylation regulates intercellular adhesion and inhibits cell transformation.
  • SHP2-mediated cell transformation is a complex process involving the modulation of RTK signaling, cell adhesion, and cytoskeletal organization.

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