Langton, P.F.; (2008) Daspp and boa regulate C-terminal Src kinase activity to control epithelial proliferation and integrity. Doctoral thesis , University of London.

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Abstract

Src-family kinases (SFKs) control a wide variety of biological processes, from cell proliferation and differentiation to cytoskeletal rearrangements. Abnormal SFK activation has been implicated in a wide variety of cancers and is associated with metastatic behaviour. SFKs are maintained in an inactive state by inhibitory phosphorylation of their C-terminal region by C-terminal Src kinase (CSK). In this study, Drosophila ASPP (dASPP) has been characterized and identified as a regulator of dCsk activity. dASPP is the homolog of the mammalian ASPP proteins, which are known to bind to and specifically stimulate the pro-apoptotic function of p53. dASPP is a positive dCsk regulator. Firstly, dASPP mutants show similar phenotypes to dCsk mutants, which are partially rescued by dSrc64B loss of function. Secondly, dASPP loss of function enhances the specific phenotypes of dCsk mutants in wing epithelial cells. Thirdly, dASPP physically interacts with dCsk to potentiate the inhibitory phosphorylation of dSrc42A. Taken together, these results suggest that dASPP has a role in maintaining epithelial integrity through dCsk regulation (Langton et al., 2007). This work also provides the initial characterization of Boa (Binder of dASPP). Boa physically interacts with dASPP and is important for maintaining high levels of dASPP at the apical membrane. This may be achieved by regulating the stability or localization of dASPP. The data suggests that Boa is important for dASPP function as it also genetically interacts with dCsk. dASPP or Boa loss of function results in similar phenotypes, although there are important differences indicating that Boa has other roles besides dASPP regulation. In another project, I have examined the transcriptional control of DIAP1 (Drosophila Inhibitor of Apoptosis 1) by the Ras pathway. Preliminary results suggest that the Ras pathway up-regulates DIAP1 transcription and this may be mediated by the Ttk69 transcription factor.

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