The protein tyrosine phosphatase Epsilon (PTPε) gene gives rise to two physiologically-distinct protein products - a transmembranal, receptor-like form and cytoplasmic, non-receptor form. Previous studies have suggested a link between expression of transmembranal PTPε and transformation of mouse mammary epithelium specifically by ras or neu, although little is known about the underlying molecular mechanisms; cytoplasmic PTPε is believed to function mainly in hematopoietic tissues. As part of our efforts to understand PTPε function at the molecular level, we demonstrate here that both forms of PTPε associate with the adaptor molecule Grb2 in vivo. Binding is mediated by the SH2 domain of Grb2; this domain binds exclusively to the carboxy-terminal phosphotyrosine of cytoplasmic PTPε(Y638), and probably to additional phosphotyrosine residues in transmembranal PTPε. Through its SH2 domain, Grb2 can constitutively associate with transmembranal PTPε in mammary tumors initiated by ras or neu, and can be induced to associate with cytoplasmic PTPε in Jurkat T-cells following stimulation of T-cell receptor signaling by pervanadate. These findings indicate that tyrosine phosphorylation of PTPε and subsequent binding to Grb may link this phosphatase to downstream events which transduce signals from the cell membrane to its interior.
Bibliographical noteFunding Information:
We gratefully acknowledge the support of Dr Philip Leder, Harvard Medical School, during the initial stages of this work. We also thank Dr Thomas M Roberts, Dana-Farber Cancer Institute, Dr Jan Sap, New York University, Dr Yosef Yarden, the Weizmann Institute of Science, and Dr Ami Aronheim, Technion-Israel Institute of Technology, for kind gifts of reagents used in this study. This research was supported by the Israel Science Foundation, founded by the Israel Academy of Sciences and Humanities, by a grant from the Leo and Julia Forchheimer Center for Molecular Genetics at the Weizmann Institute of Science, and by a Jakubskind-Cymerman Prize. A Elson is an Alon Fellow and incumbent of the Adolfo and Evelyn Blum Career Development Chair in Cancer Research at the Weizmann Institute.
- Breast cancer
- SH2 domain
- T-cell receptor
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research