CDK11 negatively regulates Wnt/β-catenin signaling in the endosomal compartment by affecting microtubule stability

Danmin Ou, Lin Chen, Jiang He, et al.

Abstract


Objectives: Improper activation of Wnt/β-catenin signaling has been implicated in human diseases. Beyond the well-studiedglycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1), other kinases affecting Wnt/β-catenin signaling remain to bedefined.

Methods: To identify the kinases that modulate Wnt/β-catenin signaling, we applied a kinase small interfering RNA (siRNA) libraryscreen approach. Luciferase assays, immunoblotting, and real-time polymerase chain reaction (PCR) were performed to confirmthe regulation of the Wnt/β-catenin signaling pathway by cyclin-dependent kinase 11 (CDK11) and to investigate the underlyingmechanism. Confocal immunofluorescence, coimmunoprecipitation (co-IP), and scratch wound assays were used to demonstratecolocalization, detect protein interactions, and explore the function of CDK11.

Results: CDK11 was found to be a significant candidate kinase participating in the negative control of Wnt/β-catenin signaling.Down-regulation of CDK11 led to the accumulation of Wnt/β-catenin signaling receptor complexes, in a manner dependent onintact adenomatosis polyposis coli (APC) protein. Further analysis showed that CDK11 modulation of Wnt/β-catenin signalingengaged the endolysosomal machinery, and CDK11 knockdown enhanced the colocalization of Wnt/β-catenin signaling receptorcomplexes with early endosomes and decreased colocalization with lysosomes. Mechanistically, CDK11 was found to function inWnt/β-catenin signaling by regulating microtubule stability. Depletion of CDK11 down-regulated acetyl-α-tubulin. Moreover,co-IP assays demonstrated that CDK11 interacts with the α-tubulin deacetylase SIRT2, whereas SIRT2 down-regulation in CDK11-depleted cells reversed the accumulation of Wnt/β-catenin signaling receptor complexes. CDK11 was found to suppress cell migrationthrough altered Wnt/β-catenin signaling.

Conclusions: CDK11 is a negative modulator of Wnt/β-catenin signaling that stabilizes microtubules, thus resulting in thedysregulation of receptor complex trafficking from early endosomes to lysosomes.

Cite this article as: Ou D, Chen L, He J, Rong Z, Gao J, Li Z, et al. CDK11negatively regulates Wnt/β-catenin signaling in the endosomal compartmentby affecting microtubule stability. Cancer Biol Med. 2020; 17: 328-342.doi: 10.20892/j.issn.2095-3941.2019.0229


Keywords


Wnt/β-catenin signaling; CDK11; endosome; microtubule; SIRT2

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