Transmodulation between phospholipase D and c-Src enhances cell proliferation.
Phospholipase D (PLD) has been implicated in the signal transduction pathways initiated by several mitogenic protein tyrosine kinases. We demonstrate for the first time that most notably PLD2 and to a lesser extent the PLD1 isoform are tyrosine phosphorylated by c-Src tyrosine kinase via direct association. Moreover, epidermal growth factor ... induced tyrosine phosphorylation of PLD2 and its interaction with c-Src in A431 cells. Interaction between these proteins is via the pleckstrin homology domain of PLD2 and the catalytic domain of c-Src. Coexpression of PLD1 or PLD2 with c-Src synergistically enhances cellular proliferation compared with expression of either molecule. While PLD activity as a lipid-hydrolyzing enzyme is not affected by c-Src, wild-type PLDs but not catalytically inactive PLD mutants significantly increase c-Src kinase activity, up-regulating c-Src-mediated paxillin phosphorylation and extracellular signal-regulated kinase activity. These results demonstrate the critical role of PLD catalytic activity in the stimulation of Src signaling. In conclusion, we provide the first evidence that c-Src acts as a kinase of PLD and PLD acts as an activator of c-Src. This transmodulation between c-Src and PLD may contribute to the promotion of cellular proliferation via amplification of mitogenic signaling pathways.
Mesh Terms:
Animals, Carcinoma, Squamous Cell, Catalytic Domain, Cell Division, Cells, Cultured, Cytoskeletal Proteins, Enzyme Activation, Epidermal Growth Factor, Female, Humans, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinases, Mutation, Paxillin, Phospholipase D, Phosphoproteins, Phosphorylation, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Rats, Signal Transduction, Tyrosine
Animals, Carcinoma, Squamous Cell, Catalytic Domain, Cell Division, Cells, Cultured, Cytoskeletal Proteins, Enzyme Activation, Epidermal Growth Factor, Female, Humans, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinases, Mutation, Paxillin, Phospholipase D, Phosphoproteins, Phosphorylation, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Rats, Signal Transduction, Tyrosine
Mol. Cell. Biol.
Date: May. 01, 2003
PubMed ID: 12697812
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