EPS8 phosphorylation by Src modulates its oncogenic functions.
EPS8 phosphorylation by Src modulates its oncogenic functions.
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DOI：
10.1038/s41416-020-0976-6
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发表时间：
2020-09
影响因子：
8.8
通讯作者：
Yeudall WA
中科院分区：
文献类型：
--
作者：
Shahoumi LA;Khodadadi H;Bensreti H;Baban B;Yeudall WA
EPS 8是调节增殖、肌动蛋白动力学和受体运输的支架蛋白。其在癌症中的表达增加，增强有丝分裂、迁移和肿瘤发生。Src在四个酪氨酸残基磷酸化EPS 8，尽管功能尚不清楚。在这里，我们研究了EPS 8酪氨酸磷酸化在HNSCC中Src靶位点的促癌作用。表达EPS 8 Src介导的磷酸化位点突变体（Y 485 F、Y 525 F、Y 602 F、Y 774 F和所有四种组合的[FFFF]）的质粒在含有正常内源水平的EPS 8的细胞中表达。此外，用达沙替尼处理细胞以抑制Src活性。通过蛋白质印迹法评估EPS 8下游靶标。伤口闭合，增殖，免疫荧光和致瘤性测定用于研究苯丙氨酸突变对EPS 8生物学功能的影响。在表达FFFF-和Y 602 F-EPS 8突变体的细胞中，FOXM 1、AURKA和AURKB减少，而携带Y 485 F-、Y 525 F-和Y 774 F-EPS 8突变体的细胞与对照相比没有显示出差异。与此一致，达沙替尼降低了EPS 8靶标的表达。此外，Y 602 F-和FFFF-EPS 8突变体减少有丝分裂和运动。然而，与对照细胞相比，FFFF-或Y 602 F-EPS 8突变体实际上促进了致瘤性。EPS 8在Y 602处的磷酸化对于细胞周期的信号传导至关重要，并且可以提供解释达沙替尼治疗疗效降低的见解。
EPS8 is a scaffolding protein that regulates proliferation, actin dynamics and receptor trafficking. Its expression is increased in cancer, enhancing mitogenesis, migration and tumorigenesis. Src phosphorylates EPS8 at four tyrosine residues, although the function is unknown. Here we investigated the pro-oncogenic role of EPS8 tyrosine phosphorylation at Src target sites in HNSCC. Plasmids expressing EPS8 Src-mediated phosphorylation site mutants (Y485F, Y525F, Y602F, Y774F and all four combined [FFFF]) were expressed in cells containing a normal endogenous level of EPS8. In addition, cells were treated with dasatinib to inhibit Src activity. EPS8 downstream targets were evaluated by western blotting. Wound closure, proliferation, immunofluorescence and tumorgenicity assays were used to investigate the impact of phenylalanine mutations on EPS8 biological functions. FOXM1, AURKA, and AURKB were decreased in cells expressing FFFF- and Y602F-EPS8 mutants, while cells harbouring the Y485F-, Y525F- and Y774F-EPS8 mutants showed no differences compared to controls. Consistent with this, dasatinib decreased the expression of EPS8 targets. Moreover, Y602F- and FFFF-EPS8 mutants reduced mitogenesis and motility. Strikingly though, FFFF- or Y602F-EPS8 mutants actually promoted tumorigenicity compared with control cells. Phosphorylation of EPS8 at Y602 is crucial for signalling to the cell cycle and may provide insight to explain reduced efficacy of dasatinib treatment.
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影响因子：
0.5
作者：
Bobdey S;Sathwara J;Jain A;Saoba S;Balasubramaniam G
通讯作者：
Balasubramaniam G
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通讯作者：
Tinhofer I
影响因子：
2.7
作者：
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通讯作者：
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影响因子：
7.6
作者：
Crowel, DL;Milo, GE;Shuler, CF
通讯作者：
Shuler, CF