Identification of a Gab1-Tribbles 2 interaction and its role in P13K/Akt signalling and cellular morphology

• Main Author: Street-Docherty, Louise Michelle
• Published: University of Sheffield 2011
• Subjects: 611.0181
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.578713

A novel family of signalling regulators, Tribbles (Trb), have been recently identified and characterised. They possess a single kinase like domain but are catalytically inactive. Numerous interacting protein partners of Tribbles have been identified; they have been highlighted to play a role in many cellular and disease processes. Gab (Grb2 associated binder) proteins play a role in signalling events induced by receptor tyrosine kinases (RTKs). Gabl is a prototypic member of this family, which has been shown to have an important function in the mechanism ofPI3K/Akt activation. I demonstrated that Gab I and Trb2 interact, a protein-protein interaction that has not been reported previously. Based on the role of Gabl and Trb proteins in the regulation of P13K/Akt signalling, I examined the Gabl-Trb2 interaction in the wider context ofP13K and AktlPKB signalling. Subsequently, I demonstrated the Gabl-Trb2 protein interaction is regulated by PI3K1 Akt signalling. The cellular actin cytoskleton, functions in the control of cell motility and proliferation, morphology, and also cell-cell communication. Thus, it is inevitable that abnormalities in its regulation result in disease processes. A role for Gab 1 has been demonstrated previously in regulation of the actin cytoskeleton and membrane ruffles in response to RTK activation. The role of Gab! and Trb2, both individually and together in the regulation of membrane ruffling and actin cytoskeleton arrangement was investigated. Novel findings are presented that implicate a role for Trb2 in cellular morphology, and initial investigations were conducted to begin elucidating the potential signaling pathways involved. Overall this study demonstrates a role for Gab 1- Trb2 interaction in PI3K1 Akt signalling and cellular morphology. P13K signalling and actin cytoskeleton dynamics play a central role in many vascular disease processes. Thus, it is possible that investigations into Trb2's role in such processes may result in the identification of novel potential therapeutic strategies. xx