Ras proteins regulate signalling pathways that control many cellular responses such as proliferation, survival and differentiation.
Ras proteins are activated when guanosine triphosphate (GTP) is bound. SOS1, and other exchange factors stimulate guanine nucleotide dissociation from Ras, which results in increased levels of Ras–GTP.
Ras–GTP signalling is terminated by hydrolysis to Ras–guanosine diphosphate (Ras–GDP), a reaction catalysed by the GTPase-activating proteins (GAPs), including p120GAP and neurofibromin.
Ras–GTP binds to various effector proteins to stimulate signalling pathways; among these effector pathways is the Raf–mitogen-activated and extracellular-signal regulated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) cascade.
Activating somatic mutations in the Ras genes and mutations that activate regulators and effectors of Ras proteins are common in tumour development and cancer.
Germline mutations that affect components of the Ras–Raf–MEK–ERK pathway are now known to underlie a group of developmental disorders, such as Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome.
Germline mutations in human syndromes frequently encode novel mutant proteins. Studies performed to date suggest that strength and/or duration of signalling through the Ras–Raf–MEK–ERK pathway regulates developmental programmes. Further structural, biochemical and functional analyses of these mutant proteins will extend our understanding of Ras signalling in development and cancer.
Ras genes are the most common targets for somatic gain-of-function mutations in human cancer. Recently, germline mutations that affect components of the Ras–Raf–mitogen-activated and extracellular-signal regulated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) pathway were shown to cause several developmental disorders, including Noonan, Costello and cardio-facio-cutaneous syndromes. Many of these mutant alleles encode proteins with aberrant biochemical and functional properties. Here we will discuss the implications of germline mutations in the Ras–Raf–MEK–ERK pathway for understanding normal developmental processes and cancer pathogenesis.
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The authors thank B. Neel for insightful discussions. Some of the research from our laboratories discussed in this article was supported by grants from the US Army Neurofibromatosis Research Program and the National Cancer Institute, and by a SCOR award from the Leukemia and Lymphoma Society of America.
Gideon Bollag is an employee of Plexxikon Inc.
- Pulmonic stenosis
A common form of congenital heart disease that frequently requires surgical correction. Pulmonic stenosis is a common feature of Noonan syndrome.
A malignant tumour that arises in chromaffin cells within the adrenal medulla.
Farnesyltransferases add farnesyl (15-carbon isoprene) groups to Ras and many other cellular proteins. This post-translational modification is essential for targeting proteins to the plasma membrane and other subcellular compartments.
- Prenyl transferases
A general class of enzymes that includes both farnesyltransferases and geranylgeranyl transferases, which transfer prenyl moieties (for example, farnesyl or geranylgeranyl groups) to cellular proteins.
Geranylgeranyl tranferases add geranylgeranyl (20-carbon isoprene) groups to cellular proteins in order to direct membrane localization. Ras proteins are not normally geranylgeranylated, but KRAS and NRAS are processed by geranylgeranyl transferases in the absence of farnesylation.
The post-translational addition of palmitate (16-carbon fatty acid) to cysteine residues on proteins to modulate membrane affinity.
- Arginine finger
A highly conserved residue in GTPase-activating proteins that directly interacts with the P loop of Ras proteins and is essential for accelerating intrinsic Ras GTPase activity.
- Second site mutations
This refers to the creation of mutant proteins that contain two independent mutations. As applied to Ras, this typically involves mutating an amino acid in the switch I or II domains in the context of an oncogenic V12 or D12 protein.
- Latent allele
Conditional mutant alleles in mice are referred to as latent because they are present in the animal and can be inducibly expressed in specific populations of cells.
This refers to an increase in the number of cells in a tissue that are generally non-transformed.
- Myeloproliferative disorder
A clonal myeloid malignancy in which there are excessive numbers of cells within one or more lineages that retain some capacity to differentiate in vivo.
- Lisch nodules
Hyperpigmented lesions in the eye that are a hallmark of NF1 disease.
A malignant tumour of connective tissue that generally arises in the extremities and is difficult to cure. This cancer is also referred to as a malignant peripheral nerve sheath tumour.
A tumour of the central nervous system that shows a range of histological and biological properties from benign (grade I) to highly malignant (grade IV).
This term refers to an abnormally large head circumference (>ninety-fifth percentile for age).
- Mast cells
Specialized haematopoietic cells derived from myeloid progenitors that are abundant in tissues and mediate local inflammatory and immunological responses.
Specialized cells within the skin that produce the pigment melanin. Melanocyte precursors are the cells of origin in melanoma.
- Schwann cells
Specialized neural crest cells within peripheral nerves that have a central role in myelination. Compelling genetic evidence supports the idea that NF1 inactivation in Schwann cells is essential for neurofibroma formation.
- Plexiform neurofibroma
A developmental lesion in individuals with NF1 that is frequently disfiguring and may cause substantial morbidity by impinging on normal anatomic structures. Plexiform neurofibromas can acquire additional genetic lesions and progress to malignant peripheral nerve-sheath tumours.
- Facial dysmorphism and craniofacial abnormalities
These terms refer to phenotypic abnormalities of the skull and face that result from an abnormal pattern of bone and cartilage development.
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Schubbert, S., Shannon, K. & Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7, 295–308 (2007). https://doi.org/10.1038/nrc2109
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