University of Dundee

Understanding the mechanisms by which specific FAM83-CK1 complexes recognise and phosphorylate substrates

University of Dundee, MRC Protein Phosphorylation and Ubiquitylation Unit, Dundee, United Kingdom

In the past few years, the Sapkota lab has discovered that FAM83 proteins interact with and regulate the subcellular distribution of the serine/threonine protein kinase CK1 isoforms (see references below). CK1 isoforms are thought to be constitutively active kinases and are known to localise to many different subcellular compartments and phosphorylate many target proteins, including transcription factors, adhesion proteins, cytoskeletal components, membrane receptors, ribosomal proteins, vesicle-associated proteins, metabolic enzymes and many other signalling molecules, in response to different signalling cues. We hypothesize that individual FAM83 proteins determine what substrates specific CK1 isoforms can phosphorylate in different subcellular compartments and control distinct biological processes. Indeed, our recent data supports the role of FAM83F and FAM83G (aka PAWS1) in Wnt signalling, and FAM83D in cell cycle progression and these roles necessitate both interaction with CK1 and its catalytic activity. This project aims to test the hypothesis that FAM83 proteins direct CK1 isoforms to specific substrates by uncovering key CK1 substrates in Wnt signalling (FAM83F- & G-dependent) and mitosis (FAM83D-dependent). 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.

The loss of FAM83-CK1 interaction appears to be important in human pathologies, as exemplified by PAWS1 mutations that cause Palmoplantar Keratoderma, which is characterised by thickening of footpads, epidermal hyperplasia and abnormal hair growth, lead to the loss in association with CK1a. Therefore, this project will potentially open up new avenues of clinical relevance. We collaborate with leading pharmaceutical companies, and so any exciting discoveries and innovative ideas that result from this project can be expedited into potential drug discovery programmes rapidly.

Please contact Gopal Sapkota (g.sapkota@dundee.ac.uk) for further details on the project.

Key references (most studies led by PhD students):

1. Fulcher, L. J. et al (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. et al (2018). PAWS1/FAM83G controls Wnt signalling through association with Casein Kinase 1 alpha. Embo reports, e44807, DOI 10.15252/embr.201744807 (PMID: 29514862)

3. Fulcher et al (2019). FAM83D directs protein kinase CK 1α to the mitotic spindle for proper spindle positioning. EMBO reports 20 (9), e47495 (PMID:31338967)

4. Wu KZL et al (2019). Pathogenic FAM83G palmoplantar keratoderma mutations inhibit the PAWS1:CK1α association and attenuate Wnt signalling. Wellcome Open Res. Sep 9;4:133. doi: 10.12688/wellcomeopenres.15403.2. eCollection 2019. (PMID: 31656861)

5. Dunbar et al (2020). FAM83F regulates canonical Wnt signalling through an interaction with CK1α

bioRxiv (https://www.biorxiv.org/content/10.1101/2020.05.25.114504v1.full)

 

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 mrcppu-phd-admin@dundee.ac.uk. The closing date for applications is 15th February 2021 with shortlisting and interviews in March 2021. Application from overseas students are welcome.

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