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Thurs 04 Apr/19 at 4:00 pm (Taha Azad, PhD candidate)

Published Mon Apr 1st 2019

a QCRI Collaborative Graduate Program in Cancer Research  presentation!

Thursday 04 April/19 at 4:00 pm.

"Identification of Novel Receptors Tyrosine Kinases (RTKs) Regulating the Hippo Signaling Pathway in Tumorigenesis"

Taha Azad, PhD candidate, Dept. of Pathology & Molecular Medicine, Queen's University

The ability of carcinogenic chemicals to damage DNA and cause mutations is well established as critical for initiation of chemical carcinogenesis. We have found that treatment of mice with a tumourigenic dose of certain carcinogens also alters DNA repair activity, and that inter-organ differences in effects on DNA repair correlate with susceptibility to the carcinogens. Issues to be resolved include: the mechanistic basis of organ-specific effects on DNA repair; the relevance of DNA repair perturbation in different carcinogen exposure paradigms; and the feasibility of upregulating DNA repair as a chemopreventive strategy.

Several studies have shown that the Hippo pathway plays an important role in tissue growth, organ size, and cell death.  Deregulation of the Hippo pathway contributes to loss of cell contact inhibition and continuing cell proliferation, which is observed during tumorigenesis. Although many studies have been done to clarify the role of the Hippo pathway in organ size control, cell proliferation and tumorigenesis, currently the connection between the Hippo pathway and its potential upstream kinase regulators is not very clear. Since the overexpression and deregulation of receptor protein kinases (RTKs) have a pivotal role in many cancers, we hypothesize that some receptor tyrosine kinases may be involved in tumorigenesis by inhibiting the Hippo pathway.  To test the hypothesis, we developed a biosensor based on split-luciferase complementation assay. To find new RTKs which regulate the Hippo pathway, gain of function and kinase-inhibitor screenings were performed. The screenings revealed several novel RTKs that regulate the Hippo pathway such as FGFR and VEGFR. Remarkably, we found three new tyrosine-phosphorylation sites on YAP, which regulate its function and stability. Our studies indicate that some RTKs also regulate the Hippo pathway through interaction or phosphorylation of LATS, YAP, and TEAD. In conclusion, these findings highlight the pivotal role of the Hippo pathway in mediating RTK-MAPK/PI3K signalling and provide a compelling rationale for targeting YAP/TAZ in RTK-driven cancer therapies.

Supervisor: Dr. Xiaolong Yang

Everyone is welcome!