Banerjee, JJ; (2016) Developmental function of Drosophila RASSF9 and RASSF10. Doctoral thesis , UCL (University College London).

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Abstract

Cell polarity is a fundamental property of most living cells, and its disruption is associated with diseases such as cancer. Members of the N-terminal RASSF protein family have been proposed to function as tumour suppressors and oncogenes, but the underlying mechanisms are not well understood. Proteomic approaches have recently linked the human N-terminal RASSFs to PP1 phosphatases, as well as its regulatory subunit ASPP and two RASSFs - RASSF9 and RASSF10 - showed additional associations to both planar cell polarity (PCP) proteins and the apical-basal polarity determinant Par3/Bazooka. This thesis investigates the developmental function of RASSF9 and RASSF10 in Drosophila. The human interaction network of RASSF9 and RASSF10 is largely conserved in Drosophila and additional interactors are revealed. In vitro both RASSFs can associate with PCP proteins and the polarity protein Bazooka. In the case of RASSF10 this work suggests a role in establishing cell polarity in the context of asymmetric cell divisions of sensory organ precursors (SOP), the progenitor cells that will give rise to the sensory bristles. Cell biological and genetic approaches provide evidence that RASSF10 functions, together with its interaction partners Dishevelled, Frizzled and Bazooka, in the initial polarisation of SOPs prior to their asymmetric division. The second part of my thesis investigates the function of the ubiquitin system at the kinetochore in relation to Spc25, which was previously characterised as a novel ubiquitin-binding protein. My data suggest that the ubiquitin-binding properties of Spc25 might be important for the stability of the KMN (Knl1/Mis12/Ndc80) network within the kinetochore complex, also supported by the findings that members of the KMN network, namely Dsn1, Nsl1 and Spc105 are ubiquitylated, giving them the potential to interact with the ubiquitin-binding domain of Spc25. Furthermore, my findings suggest that the ubiquitin system centred on the ubiquitin-binding activity of Spc25 and the KMN network is independent from ubiquitin-mediated degradation.

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