Abstract:

The seminar will explore the paradox whereby the only common community-wide cystic fibrosis (CF) mutation (Phe508del-CFTR) happened in one fetus about 5000 years ago, but today, is silently carried by about every 60th heterozygote advantage and the pleiotropy of homozygous cystic fibrosis (CF) disease are latent manifestations of the same ‘kinase-opathy’ pathway, that protects the CF-carrier at the expense of the homozygote.

This CF-disordered pathway manifests membrane-disrupted, GTP generation due to a malfunctioning metastasis suppressor/cAMP-synthesiser (high-energy phosphorylated histidine phospho-transferase, nm23/NDPK) that interacts with two constitutively active protein kinases [controlling apoptosis and energy signalling; CK2/AMPK].

My international collaborators and I hypothesise that mis-cleavage of Phe508del-CFTR generates products that latently knock-in (a dominant) allosteric action on the most pleiotropic of all kinases, casein kinase 2 (CK2). These data will be presented in a developmental context, using C. elegans and Dictyostelium to study kinase dysfunction. The seminar will end with a call for a paradigm shift to explain why a seemingly endless stream of researchers will continue to find hundreds of CF-disrupted pathways, creating disagreement on which of the basic defects is most relevant for therapy.