hERG监管和hEAG频道Src和SHP-1酪氨酸磷酸酶通过ITIM地区环核苷酸结合域。
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单叶的LC,江泽民J,王J, Newell电子战,徐弗兰克-威廉姆斯,Lam D
hERG监管和hEAG频道Src和SHP-1酪氨酸磷酸酶通过ITIM地区环核苷酸结合域。
《公共科学图书馆•综合》。2014年2月28日,9 (2):e90024。doi: 10.1371 / journal.pone.0090024。eCollection 2014。
- PubMed ID
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24587194 (在PubMed]
- 文摘
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坚毅不屈的成员K(+)频道总科(坚毅不屈/ Kv10。x, ERG / Kv11。x,麋鹿/ Kv12。x亚科)是许多细胞和组织中表达。特别是,两个原型,EAG1 / Kv10.1 KCNH1和ERG1 / Kv11.1 / KCNH2导致正常和病理功能。大量的癌细胞扩散取决于hEAG1,和在某些情况下,hERG。hERG最出名的是导致心脏动作电位,和众多频道突变“长qt综合症”。许多细胞,尤其是癌症细胞,表达Src-family酪氨酸激酶和轴马力酪氨酸磷酸酶;和酪氨酸磷酸化的失衡会导致恶性肿瘤、自身免疫性疾病和炎症性疾病。细胞离子通道贡献功能管理,在很大程度上,通过翻译后调制,尤其是磷酸化。然而,几乎没有了解具体的酪氨酸激酶和磷酸酶的角色在调节K(+)通道在其盛总科。首先,我们表明,酪氨酸激酶抑制剂,PP1,选择性抑制肽Src, Src40-58,减少hERG电流幅值,在不改变其电压依赖性或动力学。 PP1 similarly reduces the hEAG1 current. Surprisingly, an 'immuno-receptor tyrosine inhibitory motif' (ITIM) is present within the cyclic nucleotide binding domain of all EAG-superfamily members, and is conserved in the human, rat and mouse sequences. When tyrosine phosphorylated, this ITIM directly bound to and activated SHP-1 tyrosine phosphatase (PTP-1C/PTPN6/HCP); the first report that a portion of an ion channel is a binding site and activator of a tyrosine phosphatase. Both hERG and hEAG1 currents were decreased by applying active recombinant SHP-1, and increased by the inhibitory substrate-trapping SHP-1 mutant. Thus, hERG and hEAG1 currents are regulated by activated SHP-1, in a manner opposite to their regulation by Src. Given the widespread distribution of these channels, Src and SHP-1, this work has broad implications in cell signaling that controls survival, proliferation, differentiation, and other ERG1 and EAG1 functions in many cell types.