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Abstract
Cell migration is a crucial phenomenon regulating various normal physiological processes and pathological conditions. This process requires an interplay of various signalling pathways that regulate cell adhesion, cell spreading, morphogenesis and motility. One such key regulator is the membrane-bound Focal Adhesion Kinase (FAK). It was observed that phosphorylation of FAK via ERK pathway influences migration. However, the exact mechanism that integrates ERK and FAK signalling are not well understood. We recently showed that BCH (BNIP2 and Cdc42GAP Homology) domain-containing proteins such as BPGAP1 affects cell migration by controlling ERK activity via the Ras/MAPK pathway. In this thesis, we elucidate how GDAP2 (Ganglioside- induced Differentiation-Associated-Protein 2), another BCH domain-containing protein, is critical for regulating ERK-dependent FAK function and controlling cell migration. We show the importance of GDAP2 in enabling the Ras-mediated phosphorylation of FAK. In the course of the thesis, we build upon the knowledge of GDAP2 associated ERK translocation to the cytoplasm and show its effect on reducing proliferation in cells.
We also show its unique scaffolding ability, which is essential for the interaction of FAK, Src and ERK and the final hyperactivation of FAK by its phosphorylation at S910. We also demonstrate for hyperactivation of GDAP2 mediated FAK hyperactivation leads to dissociation of paxillin from the focal adhesion complex, thereby increasing its dynamic availability. This higher focal adhesion turnover leads to heightened cell motility, cell spreading and subsequent metastasis. We also performed in-ovo studies to show the effect of GDAP2 in cancerous tumour formation and also in angiogenesis.
This study shows for the first time the unique scaffolding ability of GDAP2 in integrating three essential proteins ERK, Src and FAK while also investigating its vital importance in cancer.
