Investigation of PI3K functional compensation VIA activated tyrosine kinases
Author
Demir, Melike
Advisor
Çizmecioğlu, Onur
Date
2021-01Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
Protein tyrosine kinases and serine-threonine kinases have crucial functions in cell
signaling, differentiation, motility, and proliferation. PI3K is the most deregulated
pathway in human cancers and an essential regulator of cellular proliferation. PI3K
pathway is activated via oncogenic Ras/receptor tyrosine kinases (RTKs), PTEN loss,
or activating mutations in PI3Ks. Moreover, PI3K is one of the most promising
pathways for targeted therapies. Thus, many serine-threonine or tyrosine kinases
contribute to drug resistance elicited by PI3K inhibition. In order to identify an
individual tyrosine kinase that contributes to PI3K functional compensation, the
activated tyrosine kinase library was screened and found out that ZAP70 can
compensate growth upon PI3K abrogation. This study suggests a mechanism of
activated ZAP70 mediated partial resistance in MEFs lines. Moreover, we
demonstrated the role of activated tyrosine kinase, ZAP70, in cancer cells as a tumorinitiating factor. Activated ZAP70 is able to enhance the growth ability of
untransformed cells. Also in these cells, activated ZAP70 can develop partial
resistance to PI3K inhibition. This resistance occurs via activated downstream targets
of tyrosine kinase signaling such as STAT3/MAPK axis. Furthermore, we showed that
activated ZAP70 has a high transformation capability associated with the formation of
malignant phenotype in untransformed cells. Overall, ZAP70 may be a potent driver
of proliferation and transformation in untransformed cells as well as in cancer cells.