The transmembranal and cytoplasmic forms of protein tyrosine phosphatase epsilon physically associate with the adaptor molecule Grb2.
The protein tyrosine phosphatase Epsilon (PTPepsilon) gene gives rise to two physiologically-distinct protein products - a transmembranal, receptor-like form and a cytoplasmic, non-receptor form. Previous studies have suggested a link between expression of transmembranal PTPepsilon and transformation of mouse mammary epithelium specifically by ras or neu, although little is known about the underlying molecular mechanisms; cytoplasmic PTPepsilon is believed to function mainly in hematopoietic tissues. As part of our efforts to understand PTPepsilon function at the molecular level, we demonstrate here that both forms of PTPepsilon 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 PTPepsilon(Y638), and probably to additional phosphotyrosine residues in transmembranal PTPepsilon. Through its SH2 domain, Grb2 can constitutively associate with transmembranal PTPepsilon in mammary tumors initiated by ras or neu, and can be induced to associate with cytoplasmic PTPepsilon in Jurkat T-cells following stimulation of T-cell receptor signaling by pervanadate. These findings indicate that tyrosine phosphorylation of PTPepsilon and subsequent binding to Grb may link this phosphatase to downstream events which transduce signals from the cell membrane to its interior.
Toledano-Katchalski
H
H
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Elson
A
A
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D051380:GRB2 Adaptor Protein; D006801:Humans; D019169:Jurkat Cells; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D011506:Proteins; C490825:PTPRE protein, human; D017027:Protein Tyrosine Phosphatases; C098067:Ptpre protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4