Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells.

Abstract

The receptor-type protein tyrosine phosphatase epsilon (RPTPepsilon) activates c-Src in mammary tumor cells induced in vivo by Neu. Tumor cells lacking RPTPepsilon exhibit reduced c-Src activity, appear less transformed morphologically and proliferate slower in vitro and in vivo. Expression of Src rescues most of these phenotypes, indicating that c-Src activity is important for maintaining the transformed phenotype. However, the molecular mechanisms that control activation of c-Src by RPTPepsilon are unknown. We show that Neu induces phosphorylation of RPTPepsilon exclusively at its C-terminal Y695, and that this phosphorylation is required for activation of c-Src by RPTPepsilon. Phosphorylation of RPTPepsilon does not affect its activity toward another substrate, the voltage-gated potassium channel Kv2.1, suggesting that phosphorylation directs RPTPepsilon activity toward c-Src. Phosphorylation of RPTPepsilon reduces its dimerization at the cell membrane, although this does not affect its activity significantly. RPTPepsilon is subject to strong auto- and trans-dephosphorylation, suggesting that dephosphorylation limits the activation of c-Src downstream of Neu. We conclude that an Neu-RPTPepsilon-Src signaling pathway exists in mammary tumor cells, in which phosphorylation of RPTPepsilon by Neu directs RPTPepsilon to activate c-Src. Reversible phosphorylation of RPTPepsilon at Y695 may thus function as a 'molecular switch', which affects the substrate specificity of the phosphatase.

• Authors: D Berman-Golan, A Elson
• Journal: Oncogene (Oncogene) Vol. 26 Issue 49 Pg. 7028-37 (Oct 25 2007) ISSN: 0950-9232 [Print] England
• PMID: 17486066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peptide Fragments
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-fyn
• Proto-Oncogene Proteins c-yes
• Proto-Oncogene Proteins pp60(c-src)
• Protein Tyrosine Phosphatases
• Receptor-Like Protein Tyrosine Phosphatases, Class 4

Topics

• Animals
• Female
• Fluorescent Antibody Technique
• Immunoprecipitation
• Mammary Neoplasms, Experimental (enzymology, etiology, pathology)
• Mammary Tumor Virus, Mouse (genetics)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Peptide Fragments (immunology)
• Phenotype
• Phosphorylation
• Protein Tyrosine Phosphatases (physiology)
• Proto-Oncogene Proteins c-fyn (genetics, physiology)
• Proto-Oncogene Proteins c-yes (genetics, physiology)
• Proto-Oncogene Proteins pp60(c-src) (genetics, physiology)
• Receptor, ErbB-2 (genetics)
• Receptor-Like Protein Tyrosine Phosphatases, Class 4 (genetics, metabolism)