The role of Cadherin/Rac1/gp130/Stat3 in neoplastic transformation mediated by activated Src
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Authors
Adan, Hanad
Date
Type
thesis
Language
eng
Keyword
Cadherin-11 , Stat3 , Rac1 , gp130 , Src
Alternative Title
Abstract
Results from Dr. Raptis lab previously demonstrated that engagement of cadherins, cell to cell adhesion molecules (E-, N- cadherin or cadherin-11), triggers a significant increase in levels and activity of the Rac/Cdc42 small GTPases. This is followed by secretion of IL6 family cytokines and activation of their common receptor gp130 in an autocrine manner, resulting in phosphorylation of the Signal Transducer and Activator of Transcription-3 (Stat3) on tyrosine-705. Stat3-ptyr705 then dimerizes, migrates to the nucleus and activates transcription of genes involved in cell division and survival. In this thesis, I demonstrate that mutationally activated Src527F also increases Rac1 levels in mouse Balb/c3T3 fibroblasts, leading to secretion of IL6 family cytokines and gp130 activation, triggering a Stat3-ptyr705 increase. Interestingly, our results also demonstrate that cadherin-11 is required, to preserve gp130 levels for IL6 cytokine family signalling. At the same time however, activated Src527F downregulates cadherin-11 levels, in a quantitative manner. That is, expressed to high levels, Src527F eliminates cadherin-11, hence gp130 signaling and Stat3-ptyr705, while Src527F expression to intermediate levels allows sufficient cadherin-11, hence gp130 levels for Stat3 activation. Taken together, these data establish a loop between Src, cadherin-11, gp130 and Stat3 activation, which reveals the importance of a fine balance between Src527F and cadherin-11 levels in Stat3 activation, leading to cellular survival. Cadherins are therefore emerging as potent Stat3 activators not only in their own right but also as mediators of Stat3 activation by oncogenes such as Src, a finding which could also have significant therapeutic implications.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.