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

  • Full or part time
    Dr Gopal Sapkota
  • Application Deadline
    Sunday, December 01, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

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 remains poorly understood. Our lab has identified 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 CK1 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 CK1 (4).
Excitingly, two FAM83G mutations reported to cause palmoplantar keratoderma abolish binding to CK1 and attenuate Wnt signalling, demonstrating that the disruption FAM83-CK1 association explains human pathologies (5).

We hypothesize that the FAM83 proteins direct specific CK1 isoforms 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, CK1 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 () if you need further details on the project.

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- . The closing date for applications is December 1st 2019 with interviews in January 2020.

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)

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