Department of Pathology

Dr Heike Laman

Research description

Ribbon diagrams of the FP domain of PI31 in two dimerization configurations: through the alpha helical domain (upper pair), and through the beta sheet interface (lower pair). Kirk, et al. J. Biol. Chem. 2008. 283(32):22325-35

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.