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.

Fig. 1

Ras cycles between an active GTP-bound and an inactive GDP-bound conformation. In the active state, the two switch regions, switch I and II, change their conformation allowing Ras to activate effector proteins. The intrinsic GTPase hydrolyzes a phosphate group to produce Ras·GDP. This reaction is accelerated by GTPase activating proteins (GAPs). A similar version of this figure has been previously published [61], republication with permission

Fig. 2

a Craniofacial phenotype of young children with NS, CFC, and CS aged between 10 and 18 months. Their genotypes are PTPN11 G503R, BRAF K499E, and HRAS G13C, respectively. Note the similarities of facial features, including hypertelorism, broad forehead, and low-set ears. Coarse facial features are particularly typical of CS. b The same disorders in older children and adolescents with the mutations PTPN11 N308D, MEK2 F57I, and HRAS G12S, respectively. Facial features become more distinct with age, although the similarities of the three syndromes are still evident. Courtesy of Prof. Rainer König, Frankfurt (images of CFC patients) and Prof. Kerstin Kutsche, Hamburg (images of CS patients)

Fig. 3

The Ras signaling pathway relays growth signals from activated growth factor receptors to the nucleus. Somatic mutations in several molecules of the pathway have been implicated in cancer. It is now recognized that germline mutations of identical molecules may cause disorders of the Noonan spectrum. A similar version of this figure has been previously published [61], republication with permission

Fig. 4

Model illustrating the molecular basis of how Ras signaling may be increased in patients with neurofibromatosis type 1 leading to Noonan-like feature in these patients. Although only one NF1 allele is inactive in the germline, tumors of patients with neurofibromatosis type 1 somatically lose the second, wild-type NF1 allele