Protein tyrosine phosphatase epsilon and Neu-induced mammary tumorigenesis.
Aberrant regulation of the phosphorylation of proteins on tyrosine residues is a well-established cause of cancer. Protein tyrosine phosphatases (PTPs) share in the crucial function of maintaining appropriate levels of phosphorylation of cellular proteins, making them potentially key players in regulating the transformation process. The receptor-type tyrosine phosphatase Epsilon (RPTPepsilon) participates in supporting the transformed phenotype of mammary tumor cells induced in vivo by the Neu tyrosine kinase. The phosphatase is overexpressed in mammary tumors induced in mice by a Neu transgene and expression of RPTPepsilon in mouse mammary glands leads to massive hyperplasia and associated tumorigenesis. Furthermore, cells isolated from mammary tumors induced by Neu in mice genetically lacking RPTPepsilon appear less transformed and proliferate less well than corresponding mammary tumor cells isolated from mice expressing the phosphatase. At the molecular level, RPTPepsilon dephosphorylates and activates Src and the related kinases Yes and Fyn, and the activities of these kinases are significantly reduced in tumor cells lacking RPTPepsilon. Restoring the activities of these kinases reveals that it is only the reduced activity of Src that causes the aberrant morphology and proliferation rate of tumor cells lacking RPTPepsilon. RPTPepsilon is primed to activate Src, and presumably related kinases, following its phosphorylation by Neu at Y695 within its C-terminus. This event is crucial in enabling RPTPepsilon to activate Src, but appears not to affect the activity of RPTPepsilon towards unrelated substrates. We conclude that a Neu-RPTPepsilon-Src pathway exists in mouse mammary tumor cells, in which Neu phosphorylates RPTPepsilon thereby driving the phosphatase to specifically activate Src family kinases and to assist in maintaining the transformed phenotype.
Berman-Golan
Dalia
D
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Granot-Attas
Shira
S
Elson
Ari
A
D000818:Animals; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D018719:Erb-b2 Receptor Tyrosine Kinases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4