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Activating somatic and germline mutations of closely related  RAS  genes (H, K, N) have been found in various types of cancer and in patients with developmental disorders, respectively. The involvement of the RAS signalling pathways in developmental disorders has recently emerged as one of the most important drivers in RAS research. In the present study, we investigated the biochemical and cell biological properties of two novel missense  KRAS  mutations (Y71H and K147E). Both mutations affect residues that are highly conserved within the RAS family. KRAS Y71H  showed no clear differences to KRAS wt , except for an increased binding affinity for its major effector, the RAF1 kinase. Consistent with this finding, even though we detected similar levels of active KRAS Y71H  when compared with wild-type protein, we observed an increased activation of MEK1/2, irrespective of the stimulation conditions. In contrast, KRAS K147E  exhibited a tremendous increase in nucleotide dissociation generating a self-activating RAS protein that can act independently of upstream signals. As a consequence, levels of active KRAS K147E  were strongly increased regardless of serum stimulation and similar to the oncogenic KRAS G12V . In spite of this, KRAS K147E  downstream signalling did not reach the level triggered by oncogenic KRAS G12V , especially because KRAS K147E  was downregulated by RASGAP and moreover exhibited a 2-fold lower affinity for RAF kinase. Here, our findings clearly emphasize that individual RAS mutations, despite being associated with comparable phenotypes of developmental disorders in patients, can cause remarkably diverse biochemical effects with a common outcome, namely a rather moderate gain-of-function.

Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and cardio-facio-cutaneous syndromes