FKBP14 in Notch Signalling and Drosophila Development

Presenilins (PSs) are highly conserved transmembrane proteins that form the catalytic core of the gamma-secretase complex, which cleaves a growing list of transmembrane proteins including Notch and Amyloid Precursor Protein. Autosomal dominant mutations in the genes encoding human PS have been closely linked to cases of early onset familial Alzheimer's Disease (FAD), and these FAD-linked PS mutations influence the activity of gamma-secretase. The production and maturation of gamma-secretase subunits are highly codependent, yet the mechanisms regulating assembly and activity of the complex are unclear. A screen in Drosophila identified FKBP14, an FK506-binding proteins (FKBP), as a genetic modifier of Presenilin (Psn), with FKBP14 mutants exhibiting defects typical of loss of Notch signalling. FKBPs are highly conserved and involved in a wide array of biochemical processes including protein folding, assembly, and trafficking, yet they are non-essential in yeast and their role in development of multicellular organisms remains unclear.The work presented in this thesis establishes a role for FKBP14 in multicellular development as a regulator of Notch signalling via Presenilin and the gamma-secretase complex. I show that FKBP14 mutants genetically interact with components of the Notch pathway, and that Psn-dependent gamma-secretase cleavage, a process required for Notch signalling, is reduced in FKBP14 mutants. I also identify a Notch-independent role for FKBP14 in cell viability during Drosophila development and present data establishing that both the PPIase and EF hand domains of FKBP14 are required for its function. Altogether, these data demonstrate that FKBP14 plays a critical role in development, one aspect of which includes regulating members of the Notch signalling pathway. Investigation of the role of FKBP14 in Notch signalling via its interaction with Psn, and potentially broader roles in development, may provide a greater understanding of FKBPs in multicellular signalling.Ph.D