03:09pm Monday 24 February 2020

Understanding the specificity of RAL signaling

Your lab took a different approach and is focusing on another group of molecules. Please explain.
Anna: Oncogenic mutations of the RAS GTPases have been observed in up to 30% of human cancers. These mutations destroy GTPase activity of Ras and cause the protein to be locked in its
 active form. In clinical practice, RAS mutations define a subset of patients for whom prognosis is generally poor and treatment options are really limited. To date, efforts to develop direct
antagonists of mutant Ras proteins have not been successful. So the discovery of additional mechanisms that positively or negatively regulate RAS could have profound implications for treatment of RAS mutated tumors.

Until now, the mechanisms that govern specificity of the interactions between RAS GTPases and their downstream effectors were mainly unknown. So this paper is a real breakthrough?
Michal: Once activated, Ras GTPases exert their effects through activation of a diverse set of
downstream effectors and may propagate multiple signaling pathways. Nonetheless, under specific
physiological conditions, individual GTPases engage particular effector pathways to mediate unique cellular functions. Our results provided an explanation for the paradoxical problem of how the
same small GTPase can be specifically engaged in very different cell biological responses.

What do these findings mean for cancer research in general?
Michal: Our study highlights the importance of ubiquitination in the regulation of the RAS-like GTPases. These results strongly suggest that targeting ubiquitin-dependent RAS modifications
could be exploited as a novel strategy for treatment of RAS-mutated tumors.

You collaborated with Jan Tavernier and Kris Gevaert, VIB Department of Medical Protein
Research, for this study?
Michal: We had an incredible experience working with Mathias Laga from Kris Gevaert’s group and
Sam Lievens from Jan Tavernier’s group. It would have been impossible to make progress on the
project without their efforts.

You are one of the few female group leaders at VIB. How is your experience with this?
Anna: I’ve always felt it vital for me to follow an academic career, but juggling work with young kids I find quite challenging especially when you are moving to a new country. It is incredibly difficult to operate at your maximum level as a woman and mother, since you are hampered by having significantly less time and more demands on it than your male peers, but that only makes it all the more satisfying.

Simiceks et al.
Nature Cell Biology, 2013



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