The relationship between iRhom2 and KRAS proteins

1 in 4 cancers are caused by mutations in RAS proteins, which are responsible for inducing cell signalling cascades. KRAS proteins, a subtype of RAS, can cause cancers by stimulating cell-growth proteins to be released by the cell thereby invigorating cell proliferation.

The genetics behind KRAS proteins and their involvement in tumour development is still poorly understood. Dr Matthew Freeman and his group, who discovered the iRhom2 protein (Adrain et al., 2012), have recently determined that iRhom2 is necessary for KRAS-induced cancer. The importance of iRhom2 is cancer is reinforced by the presence of cancer-causing mutations in its N-terminus, which cause tylosis with oesophageal cancer (TOC)

Matthew Freeman, Sir William Dunn School of Pathology, was recently awarded a CRUK Development Fund to further his team’s investigation into the association between KRAS and iRhoms, and their impact on the growth of cancers.

Thus far, they have found that levels of phosphorylation (addition of phosphates) to iRhoms can upregulate the activity of ADAM17, thus invigorating cancer growth. Now the team will be investigating a new hypothesis – if the phosphorylation to iRhom2 proteins is triggered by the presence of KRAS proteins. If this is the case, this opens up new potential targets for the prevention of tumour growth.

The second line of investigation of the Freeman group will be to see if the presence of these iRhom mutations also increase the likelihood of KRAS induced cancers.

By understanding iRhom2 proteins and their involvement in cancer development, we may discover new ways to use iRhom2 as a new target for KRAS-induced cancer treatments.

Using their Development Fund Award, the Freeman group will be looking at the relationship between iRhom and KRAS proteins, and how it influences the regulation of ADAM17 and the stimulation of cell growth

About the researchers

Dr Matthew Freeman investigates the cellular mechanisms that regulate signalling between cells. One of his focuses is in understanding how iRhoms regulate growth factor release in health and disease. iRhoms are part of the Rhomboid-like superfamily, which was discovered by the Freeman group as being a family containing intramembrane proteases. This superfamily is conserved across evolution and it regulates the production of extracellular signals. The Rhomboid-like superfamily is now known to be involved with many biological processes including, for example, growth factor activation, mitochondrial function, host cell invasion by parasites and bacterial physiology. Given this range of functions it is clear that this superfamily also has potential medical significance.

Matthew is currently the Head of Department for the Sir William Dunn School of Pathology at the University of Oxford.

  • Adrain, C., Zettl, M., Christova, Y., Taylor, N., and Freeman, M. (2012). Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335, 225–228.