Protein kinase A intersects Src signaling in membrane microdomains
Protein kinase A intersects Src signaling in membrane microdomains
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DOI：
10.1074/jbc.m211426200
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发表时间：
2003-05-09
影响因子：
4.8
通讯作者：
Taskén, K
中科院分区：
文献类型：
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作者：
Abrahamsen, H;Vang, T;Taskén, K
Src激酶活性的调节与C-末端调节酪氨酸Tyr（527）的磷酸化状态紧密耦合，当其被Csk磷酸化时，抑制Src。在这里，我们证明，通过前列腺素E-2-cAMP-蛋白激酶A（PKA）途径激活Csk抑制Src。这种抑制途径在耐洗涤剂的膜组分中起作用，其中cAMP升高剂激活Csk，导致Src活性的伴随降低。对Src的抑制作用依赖于抗洗涤剂膜锚定的Csk和膜微区中抑制途径的所有组分的共定位。此外，表皮生长因子诱导的Src激活和Src底物Cbl和粘着斑激酶的磷酸化被cAMP-PKA-Csk途径的激活抑制。我们提出了一种新的机制，即G蛋白偶联受体抑制Src信号通过激活Csk的cAMP-PKA依赖的方式。
Regulation of Src kinase activity is tightly coupled to the phosphorylation status of the C-terminal regulatory tyrosine Tyr(527), which, when phosphorylated by Csk, represses Src. Here, we demonstrate that activation of Csk through a prostaglandin E-2-cAMP-protein kinase A (PKA) pathway inhibits Src. This inhibitory pathway is operative in detergent-resistant membrane fractions where cAMP-elevating agents activate Csk, resulting in a concomitant decrease in Src activity. The inhibitory effect on Src depends on a detergent-resistant membrane-anchored Csk and co-localization of all components of the inhibitory pathway in membrane microdomains. Furthermore, epidermal growth factor-induced activation of Src and phosphorylation of the Src substrates Cbl and focal adhesion kinase are inhibited by activation of the cAMP-PKA-Csk pathway. We propose a novel mechanism whereby G protein-coupled receptors inhibit Src signaling by activation of Csk in a cAMP-PKA-dependent manner.