Maslova, Kseniya. Modulatory effects of T-cadherin on cell behavior and growth factor receptor activity in carcinoma cells. 2014, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10853
Classical cadherins are well recognized to be involved in cancer progression and regulation of receptor tyrosine kinase (RTK) signaling. Implication of T-cadherin, an atypical member of cadherin superfamily, in cancer progression has been documented in many cancers but mostly on genetic and epigenetic levels. Few studies have examined functional effects of T-cadherin in cancer, the molecular mechanisms of its effects are poorly understood, and whether T-cadherin regulates RTK signaling in tumor cells is unknown.
This thesis aimed at delineation of the functions of T-cadherin and molecular mechanisms of action in cutaneous squamous cell carcinoma (SCC). We found that T-cadherin loss promotes cell elongation, cell cluster disorganization, cell motility and invasive potential, while T-cadherin upregulation reduces malignant behavior of cells. T-cadherin loss increases, while T-cadherin upregulation blunts sensitivity to stimulation by EGF, manifest at the levels of ligand-induced EGFR phosphorylation/internalization, signal transduction, cell retraction and motility. Molecular mechanisms underlying functional effects of T-cadherin involve ?1 integrin activation status and the Rho family of small GTPases. Effects of T-cadherin on EGFR activity are due to altered accumulation of EGFR within lipid raft domains; T-cadherin upregulation retains, while T-cadherin loss releases EGFR from these domains. Thus, T-cadherin acts as a negative auxiliary regulator of EGFR. EGFR activation in SCC promotes T-cadherin redistribution to intercellular contacts, supporting a reciprocal nature of cross-talk between EGFR and T-cadherin. We postulated that modulation of EGFR activity by T-cadherin could be a regulatory mechanism common to other RTKs. Using prostate cancer cells DU145 (which express comparable levels of EGFR and IGF-1R) we found that T-cadherin regulates activity of both EGFR and IGF-1R and their cross talk. Therefore modulation of growth factor receptor tyrosine kinase activity and cross-talk may be a common mechanistic principle underlying T-cad-dependent control of carcinoma cell behavior. In summary, the findings of this thesis have advanced knowledge on the functional role of T-cadherin in cancer and the participating molecular mechanisms.
|Committee Members:||Fabbro, D.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Further Research Groups at DBM > Signal Transduction (Resink/Erne)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||98 Bl.|
|Last Modified:||30 Jun 2016 10:56|
|Deposited On:||29 Jul 2014 14:14|
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