The role of PDZ domain-containing proteins in Frizzled-7 receptor signalling

Bombik, Izabela Agnieszka (2015). The role of PDZ domain-containing proteins in Frizzled-7 receptor signalling. University of Birmingham. Ph.D.

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Abstract

Wnt signalling is one the most important pathways involved in embryonic development. It controls a number of processes including cellular proliferation, stem cells maintenance, cell fate decisions and establishment of tissue polarity. It is also frequently deregulated in human cancers. Frizzled-7 is a member of the Frizzled family responsible for the signal transduction in Wnt signalling. Frizzled-7 has been reported to be upregulated in several types: of cancer. Furthermore, recent reports suggest that endocytosis of Frizzled may play a critical enhancing role in Wnt signal transduction, thus facilitating cancer development. We demonstrate here that the C-terminal PDZ binding motif (PDZ-BM) of Frizzled-7 contributes to signalling triggered by the receptor. We also explore the interaction between Frizzled-7 and syntenin-1, a PDZ domain containing protein that controls endocytic trafficking of various transmembrane proteins. We demonstrate that syntenin-1 regulates Frizzled-7 cell distribution and also modulates canonical Wnt signalling in epithelial breast cancer cells. Further, we report that the C-terminal PDZ-BM of Fz7 is indispensable for the receptor interaction with a number of PDZ proteins that control protein trafficking and cell polarity. Among these PDZ proteins are LNXl and LNX2, E3 ubiquitin ligases which are known to control trafficking of transmembrane proteins. In this study we characterize the interaction between Frizzled-7 and LNX2. We demonstrate that LNX2 influences ubiquitylation of Frizzled-7 and has the ability to moderate signal transduction within the canonical Wnt pathway in breast cancer cells.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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