Adrian Gunaratne

Featured Grad Paper: Adrian Gunaratne

Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor Beta-induced epithelial-to-mesenchymal transition


Gunaratne A, Thai BL, Di Guglielmo GM.
Mol Cell Biol. 2013 Mar;33(5):874-86. doi: 10.1128/MCB.00837-12. Epub 2012 Dec 17.


Paper Summary                 

A hallmark of aggressive epithelial derived tumours (carcinomas) is the ability to break free from the primary tumour mass and ultimately metastasize to a secondary site. Epithelial cells normally share specific characteristics that physically and biochemically constrain them from independent movement. However, during tumour progression, carcinoma cells undergo several biological changes that equip them for a successful escape from the original tumour mass. Termed the epithelial to mesenchymal transition (EMT), this biological process involves a loss in epithelial cell phenotype and the subsequent acquisition of an enhanced migratory capacity characteristic of mesenchymal cells. Although EMT is a normal process during development, in cancer EMT marks a major pathological event by which a tumour is becoming more invasive.

A major signalling molecule involved in the EMT process is transforming growth factor beta (TGFb). TGFb can trigger EMT by inducing the loss of cell-cell adhesion and the rearrangement of the actin cytoskeleton – two processes which are important for cells to acquire a migratory phenotype.  Previously it has been shown that a key player in these changes is a polarity protein called Par6. TGFb receptors phosphorylate Par6 to stimulate the loss of epithelial cell junctional complexes, initiate cytoskeletal plasticity, and ultimately enhance migration, invasion, and metastasis. In the above report, we discovered that atypical protein kinase C (aPKC), was also capable of phosphorylating Par6. Interestingly, recent reports have found that aPKCi is an oncogene and is overexpressed and overactive in lung cancers. We went on to demonstrate that genetic knockdown (using siRNA) of aPKC significantly blocked EMT and migration of lung cancer cells. Furthermore, re-introducing a phoshpo-mimetic Par6 into aPKC silenced lung cancer cells rescued EMT. These results led us to conclude that oncogenic aPKC could phosphorylate Par6 to drive EMT and ultimately the enhanced motility of lung cancer cells. This work corroborates other findings that suggest that aPKC may be a potential therapeutic target in lung cancers where aPKC is an oncogene.

Bio

I completed my undergraduate course work at the University of Toronto where I was enrolled in the Forensic Biology program. I spent my fourth year thesis project working with Peel Police and BOC Edwards Canada working on a new latent fingerprint development technique. I had fun with my fourth year project because I spent quite a bit of time working at the police station and also got to go into the field on several ride-alongs...although it was nothing like CSI Las Vegas.

I came to UWO looking to get into health related research and joined the lab of Dr. John Di Guglielmo after meeting him at a Graduate Open House. I immediately knew I liked John’s lab; in my first few months as a graduate student we had more donuts than my entire year at the police station. Enjoying great food together has always been a central aspect of our lab. Currently, I am finishing up my Ph.D. project which has examined the effects of Protein Kinase C on TGFb signalling pathways. In the future, I hope to get into work with a translational/therapeutic focus. In addition to aspirations of one day becoming a quality scientist, I also hope to conduct philanthropic work alongside some of my family in Sri Lanka.


Innovation and Excellence in Research and Teaching