Phosphorylation at tyrosine 317 and 508 are crucial for PIK3CA/p110α to promote CRC tumorigenesis.
Phosphorylation at tyrosine 317 and 508 are crucial for PIK3CA/p110α to promote CRC tumorigenesis.
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DOI：
10.1186/s13578-023-01102-7
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发表时间：
2023-09-09
影响因子：
7.5
通讯作者：
Hao, Yujun
中科院分区：
文献类型：
--
作者：
Wang, Ting;Sun, Longci;Chen, Chengkun;Zhang, Yingchao;He, Baoyu;Zhang, Yanhua;Wang, Zhenghe;Xue, Hanbing;Hao, Yujun
PI 3 K/AKT信号通路在人类肿瘤的发生中起重要作用。蛋白质磷酸化对于该途径的信号转导至关重要。PIK 3CA编码PI 3 K复合物的催化亚基p110α，是人类肿瘤中最常见的突变癌基因之一。然而，PIK 3CA/p110α的磷酸化位点及其在肿瘤发生中的潜在机制在很大程度上是未知的。用质谱鉴定PIK 3CA/p110α的酪氨酸磷酸化位点。应用Crispr/CAS9策略产生Y317 F和Y508 F突变敲入细胞克隆。在体外和体内评价细胞的生长和转移能力。磷酸化蛋白质组学分析和蛋白质印迹法用于证明PIK 3CA/p110α酪氨酸磷酸化的下游信号通路。采用体外激酶试验鉴定PIK 3CA/p110α酪氨酸磷酸化激酶。PIK 3CA/p110α的酪氨酸磷酸化受到生长因子如EGF、HGF和PDGF的刺激。在PIK 3CA/p110α上鉴定出两个酪氨酸残基，Y317和Y508。Y317或Y508磷酸化是CRC肿瘤发生所必需的。p110α的Y317突变通过Src-MLC 2途径降低癌细胞的增殖、迁移和侵袭，而p110α的Y508突变损害AKT信号传导。此外，Src与p110α相互作用并磷酸化。PIK 3CA/p110α Y317和Y508磷酸化通过两条独立的途径在结直肠癌的发生中发挥重要作用。在线版本包含补充材料，可通过10.1186/s13578-023-01102-7获得。
PI3K/AKT signaling pathway plays important role in tumorigenesis of human cancer. Protein phosphorylation is crucial for signaling transduction of this pathway. PIK3CA, encoding the catalytic subunit p110α of PI3K complex, is one of the most frequently mutated oncogenes in human cancers. However, phosphorylation sites of PIK3CA/p110α and their underlying mechanism in tumorigenesis are largely unknown. Tyrosine phosphorylation sites of PIK3CA/p110α are identified with Mass-Spectrum. Crispr/CAS9 strategy is applied to generate Y317F and Y508F mutant knock-in cell clones. The growth and metastasis abilities of cells are evaluated in vitro and in vivo. Phospho-proteomics analysis and Western blots are used to demonstrate downstream signaling pathways of PIK3CA/p110α tyrosine phosphorylation. In vitro kinase assay is applied to identify the kinase of PIK3CA/p110α tyrosine phosphorylation. Tyrosine phosphorylation of PIK3CA/p110α is stimulated by growth factors such as EGF, HGF and PDGF. Two tyrosine residues, Y317 and Y508, are identified on PIK3CA/p110α. Either Y317 or Y508 phosphorylation is essential for tumorigenesis of CRC. Mutation at Y317 of p110α reduces the proliferation, migration, and invasion of cancer cells through Src-MLC2 pathway, while mutation at Y508 of p110α impairs AKT signaling. Moreover, Src interacts with and phosphorylates p110α. PIK3CA/p110α phosphorylation at Y317 and Y508 play important role in tumorigenesis of colorectal cancer through two independent pathways. The online version contains supplementary material available at 10.1186/s13578-023-01102-7.
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影响因子：
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通讯作者：
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