RAS GTPases are fundamental regulators of development and drivers of an extraordinary number of human cancers. RAS oncoproteins constitutively signal through downstream effector proteins, triggering cancer initiation, progression and metastasis. In the absence of targeted therapeutics to mutant RAS itself, inhibitors of downstream pathways controlled by the effector kinases RAF and PI3K have become tools in the treatment of RAS-driven tumours. Unfortunately, the efficacy of this approach has been greatly minimized by the prevalence of acquired drug resistance. Decades of research have established that RAS signalling is highly complex, and in addition to RAF and PI3K these small GTPase proteins can interact with an array of alternative effectors that feature RAS binding domains. The consequence of RAS binding to these effectors remains relatively unexplored, but these pathways may provide targets for combinatorial therapeutics. We discuss here three candidate alternative effectors: RALGEFs, RASSF5 and AFDN, detailing their interaction with RAS GTPases and their biological significance. The metastatic nature of RAS-driven cancers suggests more attention should be granted to these alternate pathways, as they are highly implicated in the regulation of cell adhesion, polarity, cell size and cytoskeletal architecture.
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October 2020
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Centrosomes are microtubule-organizing centres required for the asymmetric division of neural stem cells, which support neurodevelopment, as discussed in a mini-review by Robinson and colleagues (pages 2101–2115) In the cover image, microtubules are shown in yellow and neural stem cells (aPKC) are magenta. Image provided by Dorothy Lerit.
Review Article|
October 14 2020
RAS GTPase signalling to alternative effector pathways
Swati Singh;
Swati Singh
1Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada
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Matthew J. Smith
1Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada
2Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada
Correspondence: Matthew J. Smith (matthew.james.smith@umontreal.ca)
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Publisher: Portland Press Ltd
Received:
August 02 2020
Revision Received:
September 21 2020
Accepted:
September 23 2020
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem Soc Trans (2020) 48 (5): 2241–2252.
Article history
Received:
August 02 2020
Revision Received:
September 21 2020
Accepted:
September 23 2020
Citation
Swati Singh, Matthew J. Smith; RAS GTPase signalling to alternative effector pathways. Biochem Soc Trans 30 October 2020; 48 (5): 2241–2252. doi: https://doi.org/10.1042/BST20200506
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