title: An unexpected new role of mutant Ras: perturbation of human embryonic development.
abstract: The Ras signaling pathway controls important cellular responses to growth factors, and somatic mutations in RAS genes and other components of the Ras pathway, such as PTPN11 (encoding the protein-tyrosine phosphatase SHP-2) and BRAF, are found in human malignancies. Ras proteins are guanosine nucleotide-binding proteins that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. Neoplasia-associated Ras mutations frequently affect amino acids G12, G13, or Q61 and decrease the intrinsic guanosine triphosphatase (GTPase) activity by ten- to twentyfold. The GTPase activity is crucial for Ras inactivation by hydrolysis and release of a phosphate group from Ras.GTP to produce Ras.GDP. We and others have recently discovered germline mutations in the KRAS gene in individuals diagnosed with Noonan and cardio-facio-cutaneous (CFC) syndrome, two clinically overlapping disorders characterized by short stature, distinct facial anomalies, heart defects, and other abnormalities. Noonan syndrome-associated mutations V14I and T58I K-Ras activate Ras but have milder biochemical effects than somatic mutations encountered in cancers, offering an explanation why these K-Ras lesions are tolerated during embryonic development. Together with recent findings of BRAF, MEK1, and MEK2 mutations in CFC syndrome and HRAS mutations in Costello syndrome, another clinically related disorder, it has now become clear that Noonan-like features (short stature, relative macrocephaly, facial anomalies, learning difficulties) that are found in these three related disorders are a result of constitutive activation of the Ras-Raf-extracellular signal-regulated and mitogen-activated protein kinase pathway.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany. christian.kratz@uniklinik-freiburg.de
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kratz
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D013577:Syndrome; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D018631:ras Proteins