Document Detail


Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and Cardio-Facio-Cutaneous syndromes.
MedLine Citation:
PMID:  23059812     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 or 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, which 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) compared to 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 down-regulated by RASGAP and moreover exhibited a twofold 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.
Authors:
Ion C Cirstea; Lothar Gremer; Radovan Dvorsky; Si-Cai Zhang; Roland P Piekorz; Martin Zenker; Mohammad Reza Ahmadian
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-11
Journal Detail:
Title:  Human molecular genetics     Volume:  -     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Institute of Biochemistry & Molecular Biology II, Medical Faculty, Heinrich-Heine- University, Universitätsstr. 1, 40225 Düsseldorf, Germany.
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