Effect of prostate cancer-related plexin-B1 mutations on cell signalling and function.
Doctoral thesis, UCL (University College London).
Prostate cancer is one of the most common cancers in the Western world. The metastasis of prostate cancer cells is the major cause of prostate cancer-related death. Understanding which genes are altered in prostate cancer and their implications for cell signaling and function is crucial for designing therapy strategies. Our group has identified a high frequency of somatic missense mutations in the plexin-B1 gene in localized and metastatic prostate cancer. The mutations are correlated with elevated metastatic features such as increased cell invasion, adhesion and decreased cell collapse relative to wildtype. Given the fact that Sema4D/plexin-B1 regulates cell signaling through coupling with tyrosine kinases and small GTPases, I hypothesized that plexin-B1 mutations may contribute to prostate cancer cell progression through affecting these pathways. The aims of this study were to characterize the molecular features of the three mutated forms of plexin-B1, A5359G, A5653G, and T5714C and to determine how the mutations affect cell signaling. It was found, using co-immunoprecipitation assays, that none of the three mutations affected the binding of either ErbB-2 or Met to plexin-B1. Sema4D/plexin-B1 mediated cell motility depending on the stoichiometry of plexin-B1, ErbB-2 and Met in prostate cancer cells. In addition, positive evidence was found for the impact of wildtype and mutant plexin-B1 on PI3K/Akt and MAPK pathways. All the three mutants exhibited an increased binding ability to RhoD GTPase relative to wildtype in GST-pulldown assays. This increased binding to RhoD is also associated with increased cell motility as shown in transwell migration assays. My study suggests that the three mutants confer a gain of metastatic phenotype to the cells through inactivating inhibitory pathways and has lead to the construction of a new model describing the mechanism by which plexin-B1 mutations contribute to cancer progression.
|Title:||Effect of prostate cancer-related plexin-B1 mutations on cell signalling and function|
|Open access status:||An open access version is available from UCL Discovery|
Archive Staff Only