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CK1δ activity is modulated by CDK2/E- and CDK5/p35-mediated phosphorylation

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Abstract

CK1 protein kinases form a family of serine/threonine kinases which are highly conserved through different species and ubiquitously expressed. CK1 family members can phosphorylate numerous substrates thereby regulating different biological processes including membrane trafficking, cell cycle regulation, circadian rhythm, apoptosis, and signal transduction. Deregulation of CK1 activity and/or expression contributes to the development of neurological diseases and cancer. Therefore, CK1 became an interesting target for drug development and it is relevant to further understand the mechanisms of its regulation. In the present study, Cyclin-dependent kinase 2/Cyclin E (CDK2/E) and Cyclin-dependent kinase 5/p35 (CDK5/p35) were identified as cellular kinases able to modulate CK1δ activity through site-specific phosphorylation of its C-terminal domain. Furthermore, pre-incubation of CK1δ with CDK2/E or CDK5/p35 reduces CK1δ activity in vitro, indicating a functional impact of the interaction between CK1δ and CDK/cyclin complexes. Interestingly, inhibition of Cyclin-dependent kinases by Dinaciclib increases CK1δ activity in pancreatic cancer cells. In summary, these results suggest that CK1δ activity can be modulated by the interplay between CK1δ and CDK2/E or CDK5/p35. These findings extend our knowledge about CK1δ regulation and may be of use for future development of CK1-related therapeutic strategies in the treatment of neurological diseases or cancer.

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Acknowledgments

We would like to thank Dr. Mirita Franz-Wachtel (Proteome Center Tübingen, Universität Tübingen, Germany) for performing the mass spectrometric analyses. We gratefully acknowledge Annette Blatz for excellent technical support. We are also grateful for scientific assistance of Julia Richter, Vanessa Alscher, and Nadine Süßner. CI is Ph.D. Student of the International Graduate School in Molecular Medicine at Ulm University. This work was supported by Deutsche Krebshilfe, Dr. Mildred Scheel Stiftung, awarded to Uwe Knippschild (108489).

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    1. Department of General and Visceral Surgery, Surgery Centre, Ulm University Hospital, Albert-Einstein-Allee 23, 89081, Ulm, Germany

      Chiara Ianes, Pengfei Xu, Natalie Werz, Zhigang Meng, Doris Henne-Bruns, Joachim Bischof & Uwe Knippschild

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    1. Chiara Ianes
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    2. Pengfei Xu
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    3. Natalie Werz
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    Correspondence to Uwe Knippschild.

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    C. Ianes and P. Xu contributed equally to this work.

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    Ianes, C., Xu, P., Werz, N. et al. CK1δ activity is modulated by CDK2/E- and CDK5/p35-mediated phosphorylation. Amino Acids 48, 579–592 (2016). https://doi.org/10.1007/s00726-015-2114-y

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