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• W2008492030 endingPage "3040" @default.
• W2008492030 startingPage "3032" @default.
• W2008492030 abstract "Our laboratory has recently reported that the enzyme phospholipase D2 (PLD2) exists as a ternary complex with PTP1b and the growth factor receptor bound protein 2 (Grb2). Here, we establish the mechanistic underpinnings of the PLD2/Grb2 association. We have identified residues Y169 and Y179 in the PLD2 protein as being essential for the Grb2 interaction. We present evidence indicating that Y169 and Y179 are located within two consensus sites in PLD2 that mediate an SH2 interaction with Grb2. This was demonstrated with an SH2-deficient GSTGrb2 R86K mutant that failed to pull-down PLD2 in vitro. In order to elucidate the functions of the two neighboring tyrosines, we created a new class of deletion and point mutants in PLD2. Phenylalanine replacement of Y169 (PLD2 Y169F) or Y179 (PLD2 Y179F) reduced Grb2 binding while simultaneous mutation completely abolished it. The role of the two binding sites on PLD2 was found to be functionally nonequivalent: Y169 serves to modulate the activity of the enzyme, whereas Y179 regulates total tyrosine phosphorylation of the protein. Interestingly, binding of Grb2 to PLD2 occurs irrespectively of lipase activity, since Grb2 binds to catalytically inactive PLD2 mutants. Finally, PLD2 residues Y169 and Y179 are necessary for the recruitment of Sos, but only overexpression of the PLD2 Y179F mutant resulted in increased Ras activity, p44/42Erk phosphorylation and enhanced DNA synthesis. Since Y169 remains able to modulate enzyme activity and is capable of binding to Grb2 in the PLD2 Y179F mutant, we propose that Y169 is kept under negative regulation by Y179. When this is released, Y169 mediates cellular proliferation through the Ras/MAPK pathway." @default.
• W2008492030 created "2016-06-24" @default.
• W2008492030 creator A5038718059 @default.
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• W2008492030 date "2006-01-09" @default.
• W2008492030 modified "2023-10-17" @default.
• W2008492030 title "The elucidation of novel SH2 binding sites on PLD2" @default.
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• W2008492030 doi "https://doi.org/10.1038/sj.onc.1209340" @default.
• W2008492030 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3074567" @default.
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