UBC Theses and Dissertations
Myoferlin-dependent regulation of receptor tie-2 : characterization of a novel endothelial-specific anti-angiogenesis target Yu, Carol
Heart disease and cancer are the two leading causes of death worldwide. In heart disease, reperfusion of an ischemic myocardium through increased angiogenesis, or the growth of new blood vessels, is considered the ‘holy grail’ of future therapies. In contrast, inhibiting tumour growth by decreasing angiogenesis through anti-angiogenic therapies is increasingly used in cancer patients, although the therapeutic effect is only partial. Hence, a better comprehension of angiogenesis is clearly warranted. While a plethora of literature suggests that the vascular endothelial growth factor (VEGF) and angiopoietins systems are the most potent endogenous regulators of angiogenesis, an increasing number of recent studies also show that their net angiogenic effects are mostly dictated by membrane expression of their main receptors, VEGFR-2 and tie-2, respectively. Recently, endothelial cells (ECs) were unexpectedly found to express myoferlin, a muscle protein  known for its ability to regulate plasma membrane integrity . Moreover, myoferlin was found to be involved in the regulation of VEGFR-2 expression in ECs . In this work, we report that disruption of myoferlin by gene-silencing causes decreased tie-2 expression in cultured ECs. However, myoferlin disruption does not affect the transcriptional levels of tie-2 in cultured ECs. Separation of caveolae/lipid rafts from cytosol in ECs shows presence of myoferlin and tie-2 in caveolae/lipid rafts, suggesting co-localization of the two proteins to form a large signaling complex at caveoli, which are known platforms for clustering of signaling complexes. Moreover, myoferlin is present in a cancer cell model (Lewis Lung Carcinoma) and myoferlin disruption causes decreased cell proliferation, further exploring the involvement of this membrane protein in a completely different cell system. The current work identifies potential pharmacological targets for the regulation of the tie-2 system and since tie-2 expression is almost exclusively found in ECs, this work initiates the characterization of an EC-specific target that could be further exploited to modulate angiogenic responses in an in vivo model.
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