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Department of Pathology

 
Ubiquitin ligases in cancer and Parkinson’s disease

Research

Laman Research

F-box proteins (FBPs) are the substrate-recruiting subunits of SCF (Skp1-cullin1-FBP)-type E3 ubiquitin ligases, but ubiquitinated substrates have been identified for only a few of the sixty-nine FBPs identified in humans. The major aim of my laboratory’s research is to investigate how the mis-regulation of individual F-box proteins causes two human diseases, cancer and Parkinson’s disease. FBPs interact with and ubiquitinate (mono-, multi-mono-, or poly-ubiquitination) their own particular panel of substrates, usually showing a preference for post-translationally modified, often phosphorylated, proteins. In this way, signal transduction networks that utilise protein kinases (e.g., GSK3β, Cdks, IKK) can integrate a UPS response. The two best understood types of poly-ubiquitin chain linkages are those assembled on Lys48 or Lys63. Lys48 poly-ubiquitination is the most common linkage used in mammalian cells and is almost exclusively associated with targeting proteins for proteasomal degradation. Lys63 chains are generally not associated with UPS-based proteolysis but do play a major role in regulating the destruction of proteins and organelles by the lysosomal/autophagy pathway. They are also used in other cellular networks, including the DNA damage response and the NF-κB signal transduction pathway. In these instances, they are used to build scaffolds or ‘platforms’ for protein recruitment via ubiquitin binding proteins. In addition to these canonical roles, a growing body of work has identified non-canonical, SCF-independent roles for about 12% of the human FBPs, which affect diverse cellular processes as transcription, cell cycle regulation, mitochondrial dynamics and intracellular trafficking.

 

We are interested in the unusual properties of FBPs, and have focussed much of our efforts on Fbxo7, the best example of this type of FBP. We identified Fbxo7 as an assembly factor for the proto-oncogenic D-type cyclin/Cdk6 activity. This suggested Fbxo7 would also have oncogenic activity, which we showed was the case in T lymphocytes. Upon further study, we found that Fbxo7 activity with regard to cell cycle regulation is exquisitely cell-type specific, and it can also behave as a tumour suppressor. As a regulator of cell cycle, Fbxo7 also affects cellular differentiation, and we currently investigate its impact on this in a number of different cell lineages, including haematopoietic cells and neurons. Recessive point mutations in Fbxo7 cause an atypical, early-onset form of Parkinson’s disease, and we are also characterising the defects that arise in neurons harbouring these mutated forms of Fbxo7. We also study other FBPs, including Fbxl17 and Fbxl20, which are among the most frequently rearranged genes in epithelial cancers. The challenge we face is to understand the different, complex functions of this family of signal transducing effector proteins in the context of both development and disease. We aim to tease out the cellular pathways regulated by them that can be influenced to benefit patients.

  • Group Members:

    Sara Al Rawi, Rebecca Harris, Linda Lin, Bethany Mason, Lorna Simpson, Andrei Smid, Sophie Willis

Publications

Key publications: 
  1. Mason BJ & Laman H. The FBXL family of F-box proteins: variations on a theme. Open Biol. 2020 Nov;10(11):200319. Epub 2020 Nov 25. Link 
  2. Licchesi JDF, Laman H, Ikeda F, Bolanos-Garcia VM. E3 Ubiquitin Ligases: From Structure to Physiology. Front Physiol. 2020. 26 November 2020 Link
  3. Spagnol V, Oliveira CAB, Randle SJ, Passos PMS, Correia CRSTB, Simaroli NB, Oliveira JS, Mevissen TET, Medeiros AC, Gomes MD, Komander D, Laman H, Teixeira FR.The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-kappa B signaling pathway. Biochimica et Biophysica Acta. 2020 Sep 30;1865(1):129754. doi: 10.1016/j.bbagen.2020.129754. Link

  4. Rathje CC, Randle SJ, Al Rawi S, Skinner BM, Rajamundar A, Nelson DE, Johnson EEP, Bacon J, Vlazak M, Affara NA, Ellis PJ, Laman H.A conserved requirement for Fbxo7 during male germ cell cytoplasmic remodelling.  Front Physiol. 2019. Oct 10;10:1278. doi: 10.3389/fphys.2019.01278. Link. PDF. 5.

  5. Mason B, Flach S, Teixeira, FR, Manzano Garcia R, Rueda OM, Abraham JE, Caldas C, Edwards PAW. Laman H. Fbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation.  Cell Mol Life Sci. 2019 Sept 27. Link. PDF

  6. SRW Stott, SJ Randle, S al Rawi, PA Rowicka, R Harris2, B Mason, J Xia, JW Dalley, RA Barker, H Laman. Loss of FBXO7 results in a Parkinson’s-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway. J Pathol. 2019 Oct;249(2):241-254. Link. PDF.
  7. Patel SP, Randle SJ, Gibbs S, Cooke A, Laman H. Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27. Cell Mol Life Sci. 2017 Apr;74(8):1553-1566 . Link. PDF

 

Reader in Cellular and Molecular Biology
Co-Director of CRUK Cambridge Centre Postgraduate Training Programme (MRes/PhD)
Fellow & Director of Studies for Pathology and Genetics, Clare College
Graduate Admission Tutor, Clare College

Contact Details

Department of Pathology
University of Cambridge
Tennis Court Road
Cambridge
CB2 1QP
+44 (0)1223 333722
Takes PhD students
Available for consultancy

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