SMYD2 and SMYD3 regulate the MAPK pathway in pancreatic cancer

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SMYD2 and SMYD3 are lysine methyltransferases. SMYD2 monomethylates the stress response kinase MAPKAPK3 at Lys355. SMYD3 methylates MAP3K2 at K260. Both of these modifications result in increased activity of the respective kinases. In the case of MAPKAPK3 this is thought to be due to decreased protein turnover and therefore higher effective concentration in the cytoplasm. In the case of MAP3K2 the methylation is known to cause the dissociation of the inhibitor protein PP2A [1,2]. SMYD2 and SMYD3 have other protein targets which are relevant to cancer such as p53.

The activation of both kinases promotes pancreatic cancer cell growth. SMYD3 inhibition by small molecule has been shown to inhibit the growth of a wide range of cancers including pancreatic cancer in preclinical animal models [3]. SMYD2 small molecule inhibitors have been developed however they have only been tested in vitro [4]. Combination with MAP kinase inhibitors such as MEK and ERK may prove effective.

Refs

  1. Reynoird, Nicolas, Pawel K. Mazur, Timo Stellfeld, Natasha M. Flores, Shane M. Lofgren, Scott M. Carlson, Elisabeth Brambilla, et al. ‘Coordination of Stress Signals by the Lysine Methyltransferase SMYD2 Promotes Pancreatic Cancer’. Genes & Development, 17 March 2016. doi:10.1101/gad.275529.115.
  2. Mazur, Pawel K., Nicolas Reynoird, Purvesh Khatri, Pascal W. T. C. Jansen, Alex W. Wilkinson, Shichong Liu, Olena Barbash, et al. ‘SMYD3 Links Lysine Methylation of MAP3K2 to Ras-Driven Cancer’. Nature 510, no. 7504 (21 May 2014): 283–87. doi:10.1038/nature13320.
  3. Peserico, Alessia, Aldo Germani, Paola Sanese, Armenio Jorge Barbosa, Valeria di Virgilio, Raffaella Fittipaldi, Edoardo Fabini, et al. ‘A SMYD3 Small-Molecule Inhibitor Impairing Cancer Cell Growth’. Journal of Cellular Physiology 230, no. 10 (October 2015): 2447–60. doi:10.1002/jcp.24975.
  4. Nguyen, Hannah, Abdellah Allali-Hassani, Stephen Antonysamy, Shawn Chang, Lisa Hong Chen, Carmen Curtis, Spencer Emtage, et al. ‘LLY-507, a Cell-Active, Potent, and Selective Inhibitor of Protein-Lysine Methyltransferase SMYD2’. Journal of Biological Chemistry 290, no. 22 (29 May 2015): 13641–53. doi:10.1074/jbc.M114.626861.

 

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