Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling
Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling
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DOI：
10.1128/mcb.24.11.4613-4626.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Feliciello, A
中科院分区：
文献类型：
--
作者：
Cardone, L;Carlucci, A;Feliciello, A
A-激酶锚蛋白121（AKAP 121）及其剪接异构体AKAP 84锚蛋白激酶A（PKA）锚定到线粒体外膜，集中并增强环AMP信号传导到细胞器。我们发现，AKAP 121/84也结合PTPD 1，src相关的蛋白酪氨酸磷酸酶。在体内组装含有AKAP 121、PKA、PTPD 1和src的信号传导复合物。PTPD 1激活src酪氨酸激酶，并增加表皮生长因子（EGF）信号传导的幅度和持续时间。EGF受体磷酸化和下游ERK 1/2和Elk 1依赖性基因转录的激活被PTPD 1增强。缺乏催化活性的PTPD 1突变体的表达抑制了父系并下调了ERK 1/2，但不影响c-Jun N-末端激酶1/2和p38 α丝裂原活化蛋白激酶的活性。AKAP 121结合并将PTPD 1从细胞质重新分配到线粒体，并抑制EGF信号传导。我们的研究结果表明，PTPD 1是一种新的src信号的正调控因子和EGF转导途径的关键组成部分。通过结合和/或靶向线粒体上的磷酸酶，AKAP 121调节src依赖性EGF转导途径的幅度和持续性。这代表了AKAP和蛋白酪氨酸磷酸酶之间的物理和功能相互作用的第一个例子。
A-kinase anchor protein 121 (AKAP121) and its spliced isoform AKAP84 anchor protein kinase A (PKA) to the outer membrane of mitochondria, focusing and enhancing cyclic AMP signal transduction to the organelle. We find that AKAP121/84 also binds PTPD1, a src-associated protein tyrosine phosphatase. A signaling complex containing AKAP121, PKA, PTPD1, and src is assembled in vivo. PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (EGF) signaling. EGF receptor phosphorylation and downstream activation of ERK 1/2 and Elk1-dependent gene transcription are enhanced by PTPD1. Expression of a PTPD1 mutant lacking catalytic activity inhibits sire and downregulates ERK 1/2 but does not affect the activity of c-Jun N-terminal kinase 1/2 and p38alpha mitogen-activated protein kinase. AKAP121 binds to and redistributes PTPD1 from the cytoplasm to mitochondria and inhibits EGF signaling. Our findings indicate that PTPD1 is a novel positive regulator of src signaling and a key component of the EGF transduction pathway. By binding and/or targeting the phosphatase on mitochondria, AKAP121 modulates the amplitude and persistence of src-dependent EGF transduction pathway. This represents the first example of physical and functional interaction between AKAPs and a protein tyrosine phosphatase.