University of Dundee

Define the molecular mechanisms by which PAWS1 controls Wnt signalling

Wnt signalling plays a fundamental role during development and in adult tissue homeostasis. Aberrant functions of many Wnt components are associated with many human diseases, including cancer and skin disorders. The Sapkota lab recently discovered PAWS1 (a.k.a. FAM83G) as a key regulator of Wnt signalling. Furthermore, PAWS1 mutations cause Palmoplantar Hyperkeratosis, which is characterised by thickening of footpads, epidermal hyperplasia and abnormal hair growth. We have found that the association of PAWS1 with a Ser/Thr protein kinase Casein Kinase 1 alpha (CK1a) is critical for the regulation of Wnt signalling. We hypothesize that PAWS1 directs CK1a to specific subcellular compartment and substrates to control Wnt signalling. This project aims to identify key PAWS1-dependent, CK1a substrates in Wnt signalling and dissect the molecular mechanisms by which the phosphorylation of these substrates controls Wnt signalling responses in cells. The project will offer outstanding training opportunities in cutting-edge technologies in cell and molecular biology, protein chemistry, and biochemistry, including CRISPR/Cas9 genome editing, quantitative phospho-proteomics, mass-spectrometry, and fluorescence microscopy. We collaborate with leading pharmaceutical companies so that any exciting discoveries and innovative ideas can be expedited into potential drug discovery programmes. Please contact Gopal Sapkota ( if you need further details on the project.

Key references:

1. 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

2. Bozatzi, P., and Sapkota, G.P. (2018) The FAM83 family of proteins: from pseudo-PLDs to anchors of CK1 isoforms. Biochem Soc Trans, Jun 05, BST20160277; DOI: 10.1042/BST20160277

3. 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

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.

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