Table 3 Summary of expression status, function, and mechanism of CLKs in different cancer types
From: Cdc2-like kinases: structure, biological function and therapeutic targets for diseases
Kinase | Cancer type | Expression status | Identified gene function | Phenotype | Mechanism | Ref. |
|---|---|---|---|---|---|---|
CLK1 | Pancreatic ductal adenocarcinoma (PDAC) | Upregulated | Oncogene | Promoted PC cell growth and metastasis in vitro and in vivo Associated with poor prognosis in PDAC | CLK1 enhanced phosphorylation on SRSF5Ser250, which inhibited METTL14exon10 skipping while promoting Cyclin L2exon6.3 skipping to promote cancer cell metastasis and proliferation | |
Prostate cancer (PC) | Upregulated | Oncogene | Inhibition of CLK1 decreased cell proliferation and apoptosis in PC3 and DU145 cell lines CLK1 and CLK3 expression was consistently induced in hypoxic conditions in PC3 cells | Alternative splicing in cancer related genes: C ENPE, ESCO2, CKAP2, MELK, ASPH and CD164, which contributed to TG003-inhibited cell growth inhibition by targeting CLK1 CLK1 promoted cancer cell adaption to hypoxia by regulating CASP9 alternative splicing | ||
Gastric cancer | Upregulated | Oncogene | CLK1 overexpressed and promoted cell proliferation, migration, and invasion in gastric cancer | CLK1 promoted gastric cancer by modulating its related splicing machinery pathways | ||
Ovarian cancer | / | Oncogene | CLK1 phosphorylated SPF45 to elevate SPF45 expression and promote ovarian cancer migration and invasion | CLK1 phosphorylated SPF45 to increase SPF45 expression and promote SPF45-induced exon 6 exclusion of Fas mRNA in SKOV3 breast cancer cells | ||
CLK2 | Non-small cell lung cancer (NSCLC) | Upregulated | Oncogene | Promoted NSCLC occurrence and development | CLK2 overexpression promoted NSCLC growth and acted as a biomarker; miR-573 negatively regulated CLK2 expression in NSCLC | |
Breast cancer (BC) | Upregulated | Oncogene | Promoted BC growth and EMT phenotype in luminal breast cancer Pharmacological inhibition of CLK2 decreased cell growth and promoted apoptosis in an allograft model of Myc-driven spontaneous breast cancer | CLK2 overexpression generated high levels of cyclin B1, CDK1, phospho-Rb, and activated hippo signaling pathway CLK2 promoted the EMT variant of ENAH to facilitate breast tumor invasion and metastasis CLK2 inhibition changed the AS of genes involved in cell cycle, DNA repair, RNA splicing, and RNA transport pathways | ||
Glioblastoma and glioma stem-like cell (GSC) | Upregulated | Oncogene | Depletion of CLK2 expression arrested cell cycle at G1 and S phase | Knockdown of CLK2 downregulated AKT/FOXO3a/p27 signaling to interrupt cell cycle and reduce tumor growth Downregulation of CLK2 decreased the binding affinity of CLK2 with 14–3–3τ, but increased its affinity to phospho-PP2A | ||
CLK3 | Cholangiocarcinoma (CCA) | Upregulated | Oncogene | Promoted c-Myc-mediated purine synthesis in CCA | Q607R mutation of CLK3 induced USP13 Y708 phosphorylation, promoted USP13 binding to c-Myc and enhanced c-Myc activity | |
Hepatocellular carcinoma (HCC) | Upregulated | Oncogene | Increased cell proliferation, migration, and invasion in vitro and tumor development in vivo | CLK3 promoted Wnt 3a expression and activated Wnt/β-catenin cascades in HCC | ||
Hematopoietic stem cells (HSCs) | / | Oncogene | Reinforced an HSC-specific program | CLK3 effected HMGA2 isoform switching; knock-down of CLK3 decreased HMGA2-S but increased HMGA2-L through SRSF1 | ||
CLK4 | MES-TNBC | Upregulated | Oncogene | Promoted MES-TNBC cell invasion, tumor metastasis, and CSC properties | CLK4 promoted MES-TNBC by overexpression or modulation of TGF-β signaling via SMAD3 | |
ESCC | Downregulated | Suppressor | CLK4 was downregulated in ESCC cells and patient samples. The function of CLK4 in suppressing ESCC development associated with the methylation status of its promoter | CLK4 phosphorylated MITF at Y360 and blocked MITF-enhanced de novo purine synthesis and redox balance |
