TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC

Sun, Huimin; Zheng, Jianzhong; Xiao, Junhui; Yue, Juntao; Shi, Zhiyuan; Xuan, Zuodong; Chen, Chen; Zhao, Yue; Tang, Wenqi; Ye, Shaopei; Li, Jinxin; Deng, Qiumin; Zhang, Lei; Zhu, Feng; Shao, Chen

doi:10.1038/s41419-022-04909-3

Cited by 15 publications

(16 citation statements)

References 36 publications

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“…Janus kinase 2 (JAK2) mediates Burkitt lymphoma growth by phosphorylating TOPK at Y74 [32]. TOPK is also a direct downstream substrate of ERK2, which is activated by direct phosphorylation of TOPK at S32, and after activation, TOPK plays an important role in sorafenib resistance in renal cell carcinoma (RCC) [33]. In our study, the application of TOPK inhibitor OTS514 in FYN overexpressing cells could signi cantly inhibit the proliferation and migration ability of GC cells induced by FYN.…”

Section: Discussionmentioning

confidence: 81%

Phosphorylation of TOPK at Y272 by FYN enhances proliferation and metastasis of gastric cancer

Peng

Yin

Zhang

et al. 2022

Preprint

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Background FYN is a nonreceptor tyrosine kinase that regulates diverse pathological processes. The pro-cancer role of FYN in multiple malignancies has been elucidated. However, the mechanisms that FYN promotes gastric cancer(GC) progression remain largely unknown. Methods In vitro and in vivo assays were used to investigate the function of FYN. FYN, TOPK, p-TOPK expression in GC specimens were detected by immunohistochemistry. Phosphoproteomics assays identify TOPK downstream substrate molecules. The molecular mechanism was determined using COIP assays, pull-down assays, immunofluorescence co-localization assays, western blotting, 32p-labeled isotope radioautography assays, vitro kinase assays ,and TOPK knockout mice. Results FYN was found to be significantly upregulated in GC as well as in GC cells. Knockdown of FYN expression markedly attenuated the malignant phenotype of GC cells in vitro and in vivo. Mechanistically, we identified TOPK/PBK as a novel downstream substrate of FYN, FYN directly phosphorylates TOPK at Y272. One phosphospecific antibodies against Y272 was developed to validate the phosphorylation of TOPK by FYN. Moreover, the TOPK-272F mutation impaired the interaction between TOPK and FYN, leading to disappeared TOPK phosphorylation. Consistently, human GC tissues displayed increased p-TOPK(Y272), which correlated with poor survival. Phosphoproteomics results showed a significant downregulation of both HSPB1 and p-HSPB1(ser15) in TOPK-knockdown cells, which was confirmed by TOPK-konckout mice. Conclusions FYN directly binds to TOPK in GC cells and phosphorylates TOPK at the Y272, which leads to proliferation and metastasis of GC. FYN-TOPK axis facilitates GC progression by phosphorylating HSPB1 at S15. Collectively, our study elucidates the pivotal role of the FYN-TOPK-HSPB1 cascade in GC.

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Section: Discussionmentioning

confidence: 81%

Phosphorylation of TOPK at Y272 by FYN enhances proliferation and metastasis of gastric cancer

Peng

Yin

Zhang

et al. 2022

Preprint

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“…Frontiers in Genetics frontiersin.org PDZ-binding kinase (PBK) is a serine/threonine kinase belonging to the mitogen-activated protein kinase (MAPK) kinase (MAPKK) family (Sun et al, 2016). Previous studies have shown that PBK is highly trans-activated in various cancers including ovarian cancer (Ma et al, 2022), lymphoma (Wang et al, 2022), kidney cancer (Sun et al, 2022), and colon cancer (Koshino et al, 2022), which is a promising molecular target for cancer-targeted therapy. It is worth mentioning that Yang et al (2019) found that PBK was overexpressed in HCC and was associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of oncogenes and tumor-suppressor genes with hepatocellular carcinoma: A comprehensive analysis based on TCGA and GEO datasets

Zhu

Wang²,

Hu³

et al. 2023

Front. Genet.

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Aim: Existing targeted therapies for hepatocellular carcinoma (HCC) are resistant and have limitations. It is crucial to find new HCC-related target genes.Methods: RNA-sequencing data of HCC were gathered from The Cancer Genome Atlas and Gene Expression Omnibus datasets. Initially, differentially expressed genes between normal and tumor tissues were identified from four Gene Expression Omnibus datasets, GSE36376, GSE102079, GSE54236, and GSE45267. GO terms and KEGG pathway enrichment analyses were performed to explore the potential biological functions of differentially expressed genes. A PPI network was constructed by using the STRING database, and up-regulated and down-regulated hub genes were defined through 12 topological approaches. Subsequently, the correlation bounded by up-regulated genes and down-regulated genes in the diagnosis, prognosis, and clinicopathological features of HCC was analyzed. Beyond a shadow of doubt, the key oncogene PBK and tumor suppressor gene F9 were screened out, and the specific mechanism was investigated through GSEA enrichment analysis and immune correlation analysis. The role of PBK in HCC was further verified by western blot, CCK8, transwell, and tube formation experiments.Results:CDCA5, CDC20, PBK, PRC1, TOP2A, and NCAPG are good indicators of HCC diagnosis and prognosis. The low expressions of F9, AFM, and C8B indicate malignant progression and poor prognosis of HCC. PBK was found to be closely related to VEGF, VEGFR, and PDGFR pathways. Experiments showed that PBK promotes HCC cell proliferation, migration, invasion, and tube formation in HUVEC cells. F9 was negatively correlated with the degree of immune infiltration, and low expression of F9 suggested a poor response to immunotherapy.Conclusion: The role of HCC-related oncogenes and tumor-suppressor genes in diagnosis and prognosis was identified. In addition, we have found that PBK may promote tumor proliferation through angiogenesis and F9 may be a predictor of tumor immunotherapy response.

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“…ERK activation can trigger a large transcriptional programme to support cell proliferation, suppress proapoptotic factors and stimulate antiapoptotic proteins [ 38 – 40 ]. ERK2 can phosphorylate TOPK/PBK to promote tumorigenesis and participate in sorafenib resistance of renal cancer [ 41 ]; ERK2-induced PDHE1α phosphorylation and subcellular translocation promote tumor immune escape [ 42 ]. In this study, we found that TJP2 and ERK2 are also low expressed in ccRCC, and their decreased expression is also related to worse pathology and poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

ZNF582 overexpression restrains the progression of clear cell renal cell carcinoma by enhancing the binding of TJP2 and ERK2 and inhibiting ERK2 phosphorylation

Yang

Zhang

et al. 2023

Cell Death Dis

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Recent evidences have suggested that Zinc finger protein 582 (ZNF582) plays different important roles in various tumors, but its clinical role, biological function and regulatory mechanism in clear cell renal cell carcinoma (ccRCC) are still vague. Through analyzing GEO and TCGA-KIRC data and validation with local samples, we identified the low expression pattern of ZNF582 in ccRCC. Decreased ZNF582 expression is correlated with higher tumor stage and grade, distant metastasis and poor prognosis. By analyzing the DNA methylation data of ccRCC in TCGA-KIRC and using Massarray DNA methylation and demethylation analysis, we confirmed the hypermethylation status of ZNF582 in ccRCC and its negative regulation on ZNF582 expression. Using cell phenotype experiments and orthotopic kidney tumor growth models, we determined the inhibitory effect of ZNF582 overexpression on ccRCC growth and metastasis in vivo and in vitro. Mechanistically, using TMT (Tandem mass tags) quantitative proteomics test, Co-IP (Co-immunoprecipitation) and Western Blot experiments, we clarified that ZNF582 binds to TJP2 and up-regulates TJP2 protein expression. Increased TJP2 protein combines with ERK2 to promote ERK2 protein expression and suppresses the phosphorylation of ERK2, thereby inhibiting the growth and metastasis of ccRCC. In general, our findings provide the first solid theoretical rationale for targeting ZNF582/TJP2/ERK2 axis to improve ccRCC treatment.

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TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC

Cited by 15 publications

References 36 publications

Phosphorylation of TOPK at Y272 by FYN enhances proliferation and metastasis of gastric cancer

Phosphorylation of TOPK at Y272 by FYN enhances proliferation and metastasis of gastric cancer

Identification of oncogenes and tumor-suppressor genes with hepatocellular carcinoma: A comprehensive analysis based on TCGA and GEO datasets

ZNF582 overexpression restrains the progression of clear cell renal cell carcinoma by enhancing the binding of TJP2 and ERK2 and inhibiting ERK2 phosphorylation

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