IndraLab

"Therefore, we propose that CLK3-induced Y708 phosphorylation of USP13 promotes CCA progression by activating c-Myc–mediated purine synthesis."

"In cholangiocarcinoma, TGF-β signaling triggers the phosphorylation of CLK3, a serine/threonine kinase that directly phosphorylates USP13 at Y708 and facilitates USP13 interaction with c-Myc (Zhou et al., 2020); in GSCs, USP13 can enhance the stability through deubiquitinating c-Myc, activating purine synthesis mediated by c-Myc and inducing the tumorigenesis of GSCs (Fang et al., 2017); in hepatocellular carcinoma, knockdown of USP13 by shRNA can markedly downregulate c-Myc expression, resisting xenograft tumor growth of HCC (Huang et al., 2020)."

"We demonstrated that (1) a recurrent Q607R somatic substitution in CLK3 was identified in 8% of 100 human CCAs, particularly in patients with CCA metastasis; (2) the expression of CLK3 was significantly up-regulated in CCA compared with matched control tissues; (3) CLK3 knockdown significantly inhibited CCA aggressiveness in vitro and in vivo; (4) gene ontology term enrichment and MS assays indicated that high CLK3 expression in CCA patients mainly regulated nucleotide metabolism, especially purine biosynthesis; (5) mechanistically, CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, a critical purine synthesis–associated transcription factor, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes; (6) the CCA-associated CLK3-Q607R mutant induced USP13-Y708 phosphorylation and enhanced the activity of c-Myc; (7) in turn, c-Myc transcriptionally up-regulated CLK3; (8) importantly, levels of CLK3 significantly correlated with the expression of phospho-USP13-Y708, c-Myc, and ATIC in human CCA specimens; and (9) tacrine hydrochloride was identified as a potential compound to inhibit the aberrant CLK3-enhanced CCA invasiveness."

"Moreover, a recent study also found that CDC-like kinase 3 (CLK3) or the cholangiocarcinoma-associated CLK3-Q607R mutant can directly phosphorylate USP13 at Tyr708, and promote its binding to c-Myc ( xref ; xref ) ( xref )."

"USP13 stabilizes its substrate, and at the same time, the activity of USP13 is upregulated by CLK3 via promoting phosphorylation of USP13 at Tyr708, which increases its deubiquitinating enzyme activity."

"CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes."

"The phosphorylation of USP13 at Tyrosine 708 by CLK3 is required for USP13′s binding to c-Myc, which prevents its Fbxl14-mediated ubiquitination of c-Myc in glioma stem cells [ xref ]."

No evidence text available

"Notably, the CCA-associated CLK3-Q607R mutant induced USP13-Y708 phosphorylation and enhanced the activity of c-Myc."

"CLK3 mediated the phosphorylation of USP13 at Y708, promoting its binding to c-Myc, which is an important transcription factor and also known as an oncogene in many cancers [71]."

"CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes."

"CLK3 directly interacts with and phosphorylates USP13 at Y708."

"CLK3 dependent phosphorylation of USP13 at Y708 promotes CCA progression by activating c-Myc-mediated purine synthesis."

"CLK3-dependent phosphorylation of USP13 at Y708 promotes CCA progression by activating c-Myc–mediated purine synthesis."

"We then examined the physiological significance of USP13 phosphorylation by CLK3 at Y708. xref indicates that CLK3 knockdown in HuCCT1 cells strongly impaired the interaction of USP13 with c-Myc."

"Meanwhile, a gain of function somatic mutation Q607R was identified in CLK3 kinase domain, which induced USP13 Y708 phosphorylation and promoted USP13 binding to c-Myc."