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Intracellular trafficking, and function of receptor tyrosine kinases in mammary gland development

Dillon, Christian; (2002) Intracellular trafficking, and function of receptor tyrosine kinases in mammary gland development. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Receptor tyrosine kinases (RTKs) have been implicated in the normal development and tumourigenesis of the mammary gland. This thesis investigates the roles of two RTKs, the fibroblast growth factor receptor 2IIIb (FgfR-2IIIb) and the Met receptor, in the development of the mammary gland. In addition, the signals that control the trafficking of the ErbB-2 RTK within polarised epithelial cells were examined. Different experimental approaches were utilised to specifically abrogate receptor tyrosine kinase signalling within the mammary gland. Mice containing a genetic alteration of FgfR-2IIlb were used to investigate the physiological role of the receptor in the development of the embryonic and postnatal mammary glands. FgfR-2IIIb signalling was found to be crucial for the maintenance of embryonic mammary placodes. However, FgfR-2IIIb dependent and independent pathways were found to be necessary for the control of mammary placode induction. No role was identified for the receptor in postnatal mammary development. The function of the Met receptor in mammary gland development was also addressed by generating transgenic mice expressing a dominant negative form of the receptor in the mammary epithelium. These mice displayed no obvious abnormalities in mammogenesis. ErbB-2 plays key roles in normal mammary gland development and tumourigenesis. In the mammary epithelium, ErbB-2 is localised to the basolateral membrane domain where it is able to receive signals from the underlying stroma. The mechanisms regulating this asymmetric distribution were investigated using an in vitro model of epithelial cell polarity. A 10 amino acid signal located within the intracellular juxtamembrane region of ErbB-2 was identified, and shown to be necessary and sufficient for its basolateral delivery. Furthermore, a second targeting signal in ErbB-2, previously demonstrated to control ErbB-2 basolateral delivery, was compared to the juxtamembrane signal. It was demonstrated that this second signal contained a cryptic basolateral targeting motif, but did not control the basolateral targeting of ErbB-2.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Intracellular trafficking, and function of receptor tyrosine kinases in mammary gland development
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10101729
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