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Transmodulation between Phospholipase D and c-Src Enhances Cell Proliferation

机译:磷脂酶D和c-Src之间的转调可增强细胞增殖

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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.
机译:磷脂酶D(PLD)已牵涉到几种有丝分裂蛋白酪氨酸激酶引发的信号转导途径。我们首次证明,最明显的是PLD2,在较小程度上,PLD1亚型是通过直接缔合被c-Src酪氨酸激酶磷酸化的酪氨酸。此外,表皮生长因子诱导A431细胞中PLD2的酪氨酸磷酸化及其与c-Src的相互作用。这些蛋白质之间的相互作用是通过PLD2的pleckstrin同源结构域和c-Src的催化结构域进行的。与任一分子的表达相比,PLD1或PLD2与c-Src的共表达可协同增强细胞增殖。虽然PLD作为脂质水解酶的活性不受c-Src的影响,但野生型PLDs但无催化活性的PLD突变体不会显着增加c-Src激酶的活性,上调c-Src介导的paxillin磷酸化和细胞外信号调节激酶活性。这些结果证明了PLD催化活性在刺激Src信号传导中的关键作用。总之,我们提供了第一个证据,即c-Src充当PLD的激酶,而PLD充当c-Src的激活剂。 c-Src和PLD之间的这种转调可能通过有丝分裂信号通路的扩增来促进细胞增殖。

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