The CK1 family of Ser/Thr protein kinases, thought to be constitutively active, play critical roles in many cellular processes, including Wnt signalling, mitosis and circadian rhythms and are often mis-regulated in human diseases. How they are regulated remains poorly understood. Over the past few years, the Sapkota lab has uncovered the eight proteins of the FAM83 family as key regulators of the subcellular distribution of distinct CK1 isoforms (Fulcher et al, 2018). So far, we have shown that FAM83G (which we named PAWS1) mediates Wnt signalling through association with CK1a (Bozatzi et al, 2018), and PAWS1 mutations (A34E; R52P) that abolish interaction with CK1a underlie the pathogenesis of palmoplantar keratoderma (Wu et al, 2019). Similarly, FAM83F delivers CK1α to the plasma membrane to mediate canonical WNT signalling (Dunbar et al, 2021). Interestingly, lenalidomide and other thalidomide derivatives (called IMiDs), which are currently among the best-selling drugs against multiple myelomas, are known to target the degradation of CK1α. We have shown that they also degrade FAM83F via an interaction with CK1α and result in the inhibition of Wnt signalling. However, other FAM83-CK1α complexes are spared degradation by IMiDs and PAWS1 appears to protect CK1α from IMiD-induced degradation (Dunbar et al, 2021). We have also shown that FAM83D regulates mitotic spindle orientation through association with CK1α (Fulcher et al, 2019).
We are now looking for an enthusiastic PhD student to test the hypothesis that FAM83 proteins direct specific CK1 isoforms to selective substrates in cells and understand whether or how the CK1 substrate landscape changes in cells that harbour pathogenic mutants of FAM83 members, such as PAWS1-A34E in palmoplantar keratoderma. We collaborate with leading pharmaceutical companies, and so any exciting discoveries and innovative ideas that result from this project will be expedited into potential drug discovery programmes rapidly.
1. Fulcher, L. J., Bozatzi, P., Tachie-Menson, T., Cummins, T. D., Wu, K., Dunbar, K., Shrestha, S., Wood, N., Weidlich, S., Macartney, T. J., Varghese, J., Gourlay, R., Campbell, D. G., Dingwell, K. S., Smith, J. C., Bullock, A., and Sapkota, G. P. (2018) The DUF1669 domain of FAM83 family proteins anchor Casein Kinase 1 isoforms. Sci signalling, Vol. 11, Issue 531, eaao2341 DOI: 10.1126/scisignal.aao2341 (PMID-29789297).
2. Bozatzi, P., Dingwell, K. S., Wu, K., Cooper, F., Cummins, T. D., Vogt, J., Wood, N., Macartney, T. J., Varghese, J., Gourlay, R., Campbell, D. G., Smith, J. C., and Sapkota, G. P. (2018) PAWS1/FAM83G controls Wnt signalling through association with Casein Kinase 1 alpha. Embo reports, e44807, DOI 10.15252/embr.201744807 (PMID-29514862).
3. Wu KZL, Jones RA, Tachie-Menson T, Macartney TJ, Wood NT, Varghese J, Gourlay R, Soares RF, Smith JC, Sapkota GP. (2019) Pathogenic FAM83G palmoplantar keratoderma mutations inhibit the PAWS1:CK1α association and attenuate Wnt signalling. Wellcome Open Res. 2019 Sep 9;4:133. doi: 10.12688/wellcomeopenres.15403.1. eCollection 2019. (PMID-31656861)
4. Dunbar K, Jones RA, Dingwell K, Macartney TJ, Smith JC, Sapkota GP (2021). FAM83F regulates canonical Wnt signalling through an interaction with CK1α. Life Sci Alliance. Dec 24;4(2):e202000805. doi: 10.26508/lsa.202000805. (PMID: 33361109).
5. Dunbar K, Macartney TJ, Sapkota GP (2021). IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling. Life Sci Alliance. Dec 23;4(2):e202000804. doi: 10.26508/lsa.202000804. Print 2021 Feb. (PMID: 33361334).
6. Fulcher LJ, He Z, Mei L, Macartney TJ, Wood NT, Prescott AR, Whigham AJ, Varghese J, Gourlay R, Ball G, Clarke R, Campbell DG, Maxwell CA, and Sapkota GP (2019) FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning. EMBO Rep. 2019 Jul 24:e47495. doi: 10.15252/embr.201847495. (PMID-31338967)
At the MRC PPU, as well as the possibility of a PhD in one particular lab, we offer the possibility of two 4.5-month rotations in labs of their choice. A range of other projects from MRC PPU scientists are advertised on this website. Rotations provide valuable experience and help with deciding on the choice of PhD project and research group.
Please send a CV with contact details of three referees to and a cover letter, explaining why you have chosen to apply to MRC PPU, to firstname.lastname@example.org. The closing date for applications is 15th November 2021. We will chat with long-listed applicants by Zoom in November/December 2021 to select candidates to take forward. Interviews will take place in January 2022. Applications from overseas students are welcome.