非受体酪氨酸激酶Ack1的活性受其Mig6同源区酪氨酸磷酸化的调节。

IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yağmur Kan, W Todd Miller
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引用次数: 2

摘要

Ack1是一种原致癌酪氨酸激酶,与肿瘤抑制因子Mig6同源,Mig6是表皮生长因子受体(EGFR)的抑制剂。对Mig6与EGFR结合至关重要的残基在Ack1的Mig6同源区(MHR)内保守。我们测试了Ack1 MHR和激酶结构域(KD)之间的分子内相互作用是否受磷酸化调节。我们在MHR中发现了两个Src磷酸化位点(Y859, Y860)。在Ack1 KD中加入src磷酸化的MHR可增强酶活性。Src在细胞中的共表达导致Ack1活性增加;Y859/Y860的突变阻断了这种增加。总的来说,这些数据表明Ack1 MHR的磷酸化调节了它的激酶活性。Y859/Y860的磷酸化发生在脑癌、乳腺癌、结肠癌和前列腺癌中,其中Ack1的基因组扩增或体细胞突变在疾病进展中发挥作用。我们的研究结果表明,MHR磷酸化可能导致肿瘤中Ack1的失调。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Activity of the nonreceptor tyrosine kinase Ack1 is regulated by tyrosine phosphorylation of its Mig6 homology region.

Ack1 is a proto-oncogenic tyrosine kinase with homology to the tumour suppressor Mig6, an inhibitor of the epidermal growth factor receptor (EGFR). The residues critical for binding of Mig6 to EGFR are conserved within the Mig6 homology region (MHR) of Ack1. We tested whether intramolecular interactions between the Ack1 MHR and kinase domain (KD) are regulated by phosphorylation. We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity. Co-expression of Src in cells led to increased Ack1 activity; mutation of Y859/Y860 blocked this increase. Collectively, the data suggest that phosphorylation of the Ack1 MHR regulates its kinase activity. Phosphorylation of Y859/Y860 occurs in cancers of the brain, breast, colon, and prostate, where genomic amplification or somatic mutations of Ack1 play a role in disease progression. Our findings suggest that MHR phosphorylation could contribute to Ack1 dysregulation in tumours.

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来源期刊
FEBS Letters
FEBS Letters 生物-生化与分子生物学
CiteScore
6.60
自引率
2.90%
发文量
303
审稿时长
1 months
期刊介绍: FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.
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