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@ARTICLE{Cirstea:140025,
      author       = {Cirstea, I. C. and Gremer, L. and Dvorsky, R. and Zhang, S.
                      -C. and Piekorz, R. P. and Zenker, M. and Ahmadian, M. R.},
      title        = {{D}iverging gain-of-function mechanisms of two novel {KRAS}
                      mutations associated with {N}oonan and
                      cardio-facio-cutaneous syndromes},
      journal      = {Human molecular genetics},
      volume       = {22},
      number       = {2},
      issn         = {1460-2083},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {FZJ-2013-05988},
      pages        = {262 - 270},
      year         = {2013},
      abstract     = {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. KRASY71H showed no clear
                      differences to KRASwt, 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 KRASY71H when compared with wild-type protein, we
                      observed an increased activation of MEK1/2, irrespective of
                      the stimulation conditions. In contrast, KRASK147E 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
                      KRASK147E were strongly increased regardless of serum
                      stimulation and similar to the oncogenic KRASG12V. In spite
                      of this, KRASK147E downstream signalling did not reach the
                      level triggered by oncogenic KRASG12V, especially because
                      KRASK147E 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.},
      cin          = {ICS-6},
      ddc          = {570},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {452 - Structural Biology (POF2-452)},
      pid          = {G:(DE-HGF)POF2-452},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000312651800006},
      pubmed       = {pmid:23059812},
      doi          = {10.1093/hmg/dds426},
      url          = {https://juser.fz-juelich.de/record/140025},
}