Journal
CELLULAR SIGNALLING
Volume 110, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2023.110803
Keywords
Slug; Phosphorylation; Transactivation; EMT; Metastasis
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In this study, it was found that P21-activated kinase 5 (PAK5) is overexpressed in renal cell carcinoma (RCC) and promotes metastasis by enhancing epithelial-mesenchymal transition. PAK5 binds to Slug and phosphorylates it, leading to the activation of N-cadherin. Therefore, phosphorylated Slug-S87 could serve as a therapeutic target for progressive RCC.
Renal cell carcinoma (RCC) is an aggravating cancer with a poor prognosis and a high rate of metastasis. PAK5, a p21-activated kinases, has shown to be overexpressed in a variety of cancers, including RCC. In previous studies, we discovered that PAK5 regulates cell migration and invasion in RCC cell lines. However, the underlying mechanisms remain obscure. In this study, we consolidated that PAK5 confers a pro-metastatic phenotype RCC cells in vitro and exacerbates metastasis in vivo. High PAK5 expression was associated with an advanced TNM stage and a lower overall survival. Furthermore, PAK5 increases the expression level of N-cadherin. In terms of mechanism, PAK5 bound to Slug and phosphorylated it at serine 87. As a result, phosphorylated Slug transactivated N-cadherin, accelerating the epithelial-mesenchymal transition. Collectively, Slug is a novel PAK5 substrate, and PAK5-mediated phosphorylation of Slug-S87 increases N-cadherin and the pro-metastatic phenotype of RCC, implying that phosphorylated Slug-S87 could be a therapeutic target in progressive RCC.
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