Oncogenic mutations of Ras, which are found in human tumours, tumour cell lines and in carcinogen-induced experimental tumours, cause the hyper-activation of the Ras proteins.
Ras proteins are GTPases that shuttle between the inactive GDP-bound and the active GTP-bound states. This nucleotide switching is regulated by guanine nucleotide exchange factors (GEFs), which favour the accumulation of RasGTP, and GTPase-activating proteins (GAPs), which facilitate GTP hydrolysis. Oncogenic mutations of Ras proteins are GAP-insensitive and are chronically active.
Active GTP-bound Ras proteins activate signalling pathways by engaging partners called effectors. These effectors initiate a cascade of signal transduction events that control processes, such as gene expression, cell-cycle progression, membrane trafficking, motility and survival.
De-regulated Ras signalling causes a series of congenital developmental disorders collectively known as cardio-facio-cutaneous syndromes. These diseases include neurofibromatosis type-1, Costello and Noonan syndromes, and are characterized by the accumulation of sporadic tumours, as well as skeletal, cardiac and visual abnormalities.
The enzymes involved in the post-translational processing of Ras have been attractive drug targets for cancer therapy. Among them are the farnesyltransferase inhibitors (FTIs), which inhibit the critical farnesylation reaction.
Extensive research on the Ras proteins and their functions in cell physiology over the past 30 years has led to numerous insights that have revealed the involvement of Ras not only in tumorigenesis but also in many developmental disorders. Despite great strides in our understanding of the molecular and cellular mechanisms of action of the Ras proteins, the expanding roster of their downstream effectors and the complexity of the signalling cascades that they regulate indicate that much remains to be learnt.
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We thank C. Der for comments on the manuscript and G. Bell for help in structural configurations. The authors' research is supported, in part, by the Breast Cancer Research Foundation (R.A.W), National Institues of Health (NIH) P01 CA08111 (R.A.W.), NIH U54 CA12515 (R.A.W.), NIH SPORE P50 CA089393 (R.A.W.), Susan Komen Breast Cancer Foundation (A.E.K.), Harvard Specialized Program for Research Excellence (A.E.K.), Whitehead Institute-Genzyme fellowship (A.E.K.) and the Ludwig Center for Molecular Oncology at Massachusetts Institue of Technology, USA.
- Rous sarcoma virus
(RSV). A retrovirus that was discovered in 1916 by Peyton Rous by injecting a cell-free extract of chicken tumour into healthy chickens. The extract was found to induce oncogenesis in Plymouth Rock chickens.
- G proteins
A family of proteins involved in second messenger cascades. They function as molecular switches, alternating between an inactive GDP-bound and active GTP-bound state.
- GTPase-activating protein
(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs negatively regulate GTPases by converting them from active (GTP bound) to inactive (GDP bound).
- Guanine nucleotide-exchange factor
(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.
The induction of programmed cell death by the detachment of cells from the extracellular matrix.
- Lipid raft
A membrane microdomain that is enriched in cholesterol, sphingolipids and lipid-modified proteins, such as glycosyl phosphatidylinositol (GPI)-linked proteins and palmitoylated proteins. These microdomains often function as platforms for signalling events.
- Cardio-facio-cutaneous diseases
Congenital developmental disorders caused by disregulated Ras signalling. These diseases are characterized by the accumulation of sporadic tumours as well as skeletal, cardiac and visual abnormalities.
- Neural crest
A group of embryonic cells that separate from the embryonic neural plate and migrate, giving rise to the spinal and autonomic ganglia, peripheral glia, chromaffin cells, melanocytes and some haematopoietic cells.
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Karnoub, A., Weinberg, R. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9, 517–531 (2008). https://doi.org/10.1038/nrm2438
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