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Title: Studies on the signalling of the small GTPase Rap1
Author: Verma, Sunil Kumar
ISNI:       0000 0001 3546 3580
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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RaplA (Krev-l) is a member of the Ras superfamily of small GTP-binding proteins and has highest homology to Ras. Rapl behaves as an antagonist of oncogenic K-Ras activity in NIH3T3 cells and of polyoma middle-T antigen in Rat-2 cells. It inhibits transformation of human prostate cancer cells, hamster pancreatic adenocarcinoma cells and of ethylcarbamate induced lung adenomas in transgenic mice. However, it does not prevent Ras induced transformation in human HT1080, EJ30 or SW48 cells. Rapl also plays a critical role in regulation of normal morphogenesis in the eye disk and the ovary during embryo development. Recently, Rapl has been implicated in integrin-mediated . adhesion through RapL and modulation of the actin cytoskeleton through RIAM. The downstream effectors through which Rapl mediates its diverse effects are largely unknown. Screening the human genome based upon structural and functional information from the known effectors of Rapl such as RapL, RaIGDS, RIAM and Kritl, a series of potential effectors of Rapl have been identified. Using classical and modem biochemical approaches, it has been established that RASSFlA, a well-known tumour suppressor of human carcinogenesis, is a novel effector of RaplA - linking RaplA to microtubules. Moreover, Rapl association influences the effect of RASSFIA on microtubule behaviour. It is shown that interaction between RASSFIA and RaplA is modulated by RASSFIA phosphorylation. In silica analyses on RASSFIA predicted various putative phosphorylation sites and associated protein kinases within and outside the RA domain of RASSFIA. The sites S197 and S203 within the RA domain of RASSFIA were established as novel PKC phosphorylation sites by in vitro and in vivo assays. These two sites were, however, not responsible for the regulated interaction of RASSFIA with RaplA. This study provides important new insights into the signalling of RaplA indicating that regulated association with RASSFIA links RaplA to microtubules and that the RaplA-RASSFIA interaction plays a role in microtubule dynamics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available