Insulin-like growth factor receptor activity in cancer biology & therapy responses

The Insulin-like Growth Factor 1 Receptor (IGF-1R) has an essential function in normal cell growth and in cancer progression. However, anti-IGF-1R therapies have mostly been withdrawn from clinical trials owing to a lack of efficacy and predictive biomarkers. IGF-1R activity and signalling in cancer cells is regulated by its C-terminal tail, and in particular, by a motif that encompasses tyrosines 1250 and 1251 flanked by serines 1248 and 1252 (1248- SFYYS-1252). Mutation of Y1250/1251 greatly reduces IGF-1-promoted cell migration, interaction with the scaffolding protein RACK1 in the context Integrin signalling, and IGF- 1R kinase activity. Here we investigated the phosphorylation of the SFYYS motif and characterise the conditions under which this motif may be phosphorylated under. As phosphorylated residues, the SFYYS motif may also serve to recruit interacting proteins to the IGF-1R. To this end we identified a novel IGF-1R interacting partner which requires phosphorylated residues in the SFYYS motif to interact with the IGF-1R. This interaction was found to be IGF-1-dependent, and required the scaffold protein RACK1. The interaction of this binding protein with the IGF-1R likely functions to promote maximal phosphorylation of Shc and ERK in IGF-1-stimulated cell migration, and may be important for IGF-1 signalling in cancer cells. Lastly, we have investigated possible kinases that may confer resistance or sensitivity to the IGF-1R kinase inhibitor BMS-754807. In this screen we identified ATR as a mediator of resistance and showed that suppression or chemical inhibition of ATR synergised with BMS-754807 to reduce colony formation. This work has contributes to our understanding of IGF-1R kinase regulation and signalling and suggests that administration of anti-IGF-1R drugs with ATR inhibitors may have therapeutic benefit.

Diffusible Signal Factor (DSF)-dependent quorum sensing in pathogenic bacteria and its exploitation for disease control

Cell-to-cell signals of the Diffusible Signal Factor (DSF) family are cis-2-unsaturated fatty acids of differing chain length and branching pattern. DSF signalling has been described in diverse bacteria to include plant and human pathogens where it acts to regulate functions such as biofilm formation, antibiotic tolerance and the production of virulence factors. DSF family signals can also participate in interspecies signalling with other bacteria and interkingdom signaling such as with the yeast Candida albicans. Interference with DSF signalling may afford new opportunities for the control of bacterial disease. Such strategies will depend in part on detailed knowledge of the molecular mechanisms underlying the processes of signal synthesis, perception and turnover. Here, I review both recent progress in understanding DSF signalling at the molecular level and prospects for translating this knowledge into approaches for disease control.

Harnessing bacterial signals for suppression of biofilm formation in the nosocomial fungal pathogen Aspergillus fumigatus

Faced with the continued emergence of antibiotic resistance to all known classes of antibiotics, a paradigm shift in approaches toward antifungal therapeutics is required. Well characterized in a broad spectrum of bacterial and fungal pathogens, biofilms are a key factor in limiting the effectiveness of conventional antibiotics. Therefore, therapeutics such as small molecules that prevent or disrupt biofilm formation would render pathogens susceptible to clearance by existing drugs. This is the first report describing the effect of the Pseudomonas aeruginosa alkylhydroxyquinolone interkingdom signal molecules 2-heptyl-3-hydroxy-4-quinolone and 2-heptyl-4-quinolone on biofilm formation in the important fungal pathogen Aspergillus fumigatus. Decoration of the anthranilate ring on the quinolone framework resulted in significant changes in the capacity of these chemical messages to suppress biofilm formation. Addition of methoxy or methyl groups at the C5–C7 positions led to retention of anti-biofilm activity, in some cases dependent on the alkyl chain length at position C2. In contrast, halogenation at either the C3 or C6 positions led to loss of activity, with one notable exception. Microscopic staining provided key insights into the structural impact of the parent and modified molecules, identifying lead compounds for further development.