University of Dundee

Controlling the uncontrollables: How FAM83 proteins regulate the serine/threonine protein kinase CK1 family in cells

The members of the CK1 family of kinases, thought to be constitutively active, control a plethora of cellular processes, including cell cycle progression, circadian rhythms, and Wnt signalling, yet how they are controlled to allow such diversity in impact remains poorly understood. Our lab has identified the eight members of the FAM83 family of poorly characterised proteins as key determinants of subcellular distribution of different members of the CK1 family (1,2). Specifically, we have shown that FAM83D delivers CK1a to the mitotic spindle for ensuring proper spindle orientation and cell cycle (3). We have also shown that FAM83G (aka PAWS1) drives Wnt signalling through association with CK1a (4). Excitingly, two FAM83G mutations reported to cause palmoplantar keratoderma both abolish binding to CK1a and attenuate Wnt signalling, demonstrating for the first time that the disruption FAM83-CK1 association explains human pathologies (5).

We hypothesize that the FAM83 proteins direct specific CK1 isoforms that they interact with to specific subcellular compartments and substrates, thereby controlling the phosphorylation of key CK1 substrates. This project aims to tackle this hypothesis in two ways: i. Define the molecular basis of the FAM83-CK1 interaction through X-ray crystallography, and ii. Identify and validate key FAM83D-dependent, CK1a substrates in mitosis. 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, X-ray crystallography, 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 (g.sapkota@dundee.ac.uk) if you need further details on the project.

Key references:

1. Fulcher 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

2. Bozatzi et al (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 et al (2019) FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning. EMBO Rep. 20(9):e47495. doi: 10.15252/embr.201847495.

4. Bozatzi et al (2018) PAWS1/FAM83G controls Wnt signalling through association with Casein Kinase 1 alpha. Embo reports, e44807, DOI 10.15252/embr.201744807

5. Wu et al (2019) Pathogenic FAM83G palmoplantar keratoderma mutations inhibit the PAWS1:CK1α association and attenuate Wnt signalling. Wellcome Open Research 4:133 (https://doi.org/10.12688/wellcomeopenres.15403.1)

Eligibility