7. Cascade of RAS-driven tumorigenesis
When RAS is switched on
by incoming signals, it
automatically switches on
other proteins which
ultimately turn on genes
involved in cell growth,
differentiation and survival.
8. It results…
• That mutations of RAS genes can lead to the production of permanently activated RAS
protein and the cancer will develop.
• Also, for this reason RAS inhibitors are being studied as a treatment for cancer and
other diseases with RAS overexpression.
Reference:http://journal.hep.com.cn/fib/EN/
10.1007/s11515-014-1299-x
9. Conclusions
1) Increased SMYD3 activity => methylated
MAP3K2 .: inhibiting PP2A => promoting
efficiency of signalling activation
2) SMYD3 controls efficiency of Ras-driven
tumorigenesis
3) Lysine methylation and protein phosphorylation
regulate the key signal transduction pathways in
the cytoplasm
4) Therapy using pharmacologic intervention via
inhibitors
10. Further Research
The key question emerging from the work of Mazur et al.,
(2014) is how does oncogenic RAS connect biochemically
to SMYD3->MAP3K2 activation to regulate the magnitude
of MEK1/2->ERK1/2 signalling in cancer cells?
Unclear why SMYD3 levels are elevated in Ras-mutated
cancers
2 possibilities: gene transcription OR protein stability
Peserico et al., (2015) found that SMYD3 affects cell
proliferation in breast cancer
.: investigate specificity of MAP3K2 methylation by
SMYD3 in breast cancer cells
11. References
Deuker, M.M., McMahon, M. (2015). Methylation Matters In KRAS Oncogenesis. Nature, 510(7504). p.225-
226. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250228/ [Accessed: 5 October 2015].
Goodsell,D.S. (1999). The Molecular Perspective: The ras Oncogene. The Oncologist , 4(3). p.263-264.
Available from: http://theoncologist.alphamedpress.org/content/4/3/263.full [Accessed: 5 October 2015]
Hamamoto, R., Furukawa, Y., Morita, M., Iimura, Y., Silva, F.P., Li, M., Yagyu, R., Nakamura, Y. (2004).
SYMD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nature Cell Biology,
6(8). p.731-740. Available from: http://www.nature.com/ncb/journal/v6/n8/full/ncb1151.html [Accessed: 5
October 2015]
Mazur, P.K, Reynoird, N., Khatri, P., Jansen, P., Wilkinson, A.W., Liu, S., Barbash, O., Van Aller, G.S.,
Huddleston, M., Dhanak, D., Tummino, P.J., Kruger, R.G., Garcia, B.A., Butte, A.J,, Vermeulen, M., Sage, J.,
Gozani, O. (2014). SMYD3 links lysine methylation of MAP3K2 to Ras-driven Cancer. Nature, 510(7504).
p.283-287. Available from: http://www.nature.com/nature/journal/v510/n7504/full/nature13320.html [Accessed:
5 October 2015].
Pelkmans, L., Zerial, M. (2005). Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae.
Nature, 436. p.128-133. Available from:
http://www.nature.com/nature/journal/v436/n7047/full/nature03866.html [Accessed: 5 October 2015]
Peserico, A., Germani, A., Sanese, P., Barbosa, A., Di Virgilio, V., Fittipaldi, R., Fabini, E., Bertucci, C., Varchi,
G., Moyer, M., Caretti, G., Del Rio, A. and Simone, C. (2015). A SMYD3 Small-Molecule Inhibitor Impairing
Cancer Cell Growth. J. Cell. Physiol., 230(10), pp.2447-2460. Available at: http://10.1002/jcp.24975
[Accessed 8 Oct. 2015].
