期刊
CELL REPORTS
卷 37, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.110127
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资金
- National Natural Science Foundation of China [31571457, 31771553, 31970741, 81602564]
- Ministry of Educa-tion Innovation Team Development Plan [IRT_17R107, IRT13101]
- Project of Science and Technology Department of Liaoning Province [2019JH8/10300014]
This study revealed the important role of PAK5 in breast cancer, with PAK5 deficiency inhibiting breast tumor formation. Phosphorylation of DDX5 is a substrate of PAK5, promoting breast cancer cell proliferation and metastasis. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5, enhancing microRNA biogenesis.
P21-activated kinase 5 (PAK5) plays an important role in tumors. However, the functional role of PAK5 in mammary tumorigenesis in vivo remains unclear. Here, we show that PAK5 deficiency represses MMTV-PyVT-driven breast tumorigenesis. DEAD-box RNA helicase 5 (DDX5) is a substrate of PAK5, which is phosphorylated on threonine 69. PAK5-mediated DDX5 phosphorylation promotes breast cancer cell proliferation and metastasis. The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. Finally, we verify decreased expression of DDX5 phosphorylation and sumoylation and mature miR-10b in PAK5(-/-)/MMTV-PyVT transgenic mice. Our findings provide insights into the function of PAK5 in microRNA (miRNA) biogenesis, which might be a potential therapeutic target for breast cancer.
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