Understanding the roles of Wnt signaling pathway planar-cellpolarity (PCP) proteins - DAAM1, RhoA and Dishevelled in actin cytoskeletal dynamics

Mahanta, Biswaprakash (2019) Understanding the roles of Wnt signaling pathway planar-cellpolarity (PCP) proteins - DAAM1, RhoA and Dishevelled in actin cytoskeletal dynamics. Masters thesis, Indian Institute of Science Education and Research Kolkata.

PDF (MS dissertation of Biswaprakash Mahanta (14MS046)) 14MS046.pdf - Submitted Version Restricted to Repository staff only Download (12MB)

Abstract

Wnt signalling is instrumental in regulating important developmental processes by governing cellular proliferation, migration & fate specification, all processes where cytoskeletal dynamics and reorganisation play key role. Having implications in several diseases such as breast & prostate cancer, glioblastoma and diabetes etc., the pathway has been studied primarily concentrated on the canonical β-catenin pathway. However many recent studies conducted show that the non-canonical branch is essential for generating and maintaining Planar-Cell-Polarity (PCP), thus regulating many developmental processes such as convergent extension, gastrulation and cardio-genesis etc. The studies done so far have demonstrated the importance of the PCP proteins: Dishevelled (Dvl), DAAM1 and RhoA; however they have not been able to conclusively elucidate the mechanism with which the activation is regulated involving these three proteins. The nature of interaction between the three proteins is key to understanding the uncovered regulatory phenomena, and to elucidate the downplayed role of the formin protein DAAM1 as an effector rather than just an adaptor. Protein constructs of DAAM1 and RhoA were purified aiming to study this interaction in vitro. Using biochemical tools, analysis of the autoinhibition of DAAM1 in affecting actin filament nucleation was carried out. The role of RhoA in affecting this autoinhibitory nature of DAAM1 has been studied, which hint at clarifying the conflicting viewpoints present today. Steps have been taken to express and purify Dvl2 in insect cells, which will be used to investigate the role of Dvl2 in this interactive activation mechanism.

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