RASs

Definition: The RAS gene family encodes membrane-associated, guanine nucleotide-binding proteins (GTPases) that are involved in the control of cellular proliferation and differentiation.

RAS proteins are monomeric GTPases that act as binary molecular switches to regulate a wide range of cellular processes.

The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which regulate the activation state of RAS without covalently modifying it.

By contrast, post-translational modifications (PTMs) of RAS proteins direct them to various cellular membranes and, in some cases, modulate GTP-GDP exchange.

Important RAS PTMs include the constitutive and irreversible remodelling of its carboxy-terminal CAAX motif by farnesylation, proteolysis and methylation, reversible palmitoylation, and conditional modifications, including phosphorylation, peptidyl-prolyl isomerisation, monoubiquitylation, diubiquitylation, nitrosylation, ADP ribosylation and glucosylation. (22189424)

Similar to other guanine-binding proteins (such as the heterotrimeric G proteins), the RAS proteins cycle between an active guanosine-triphosphate (GTP) bound form and an inactive, guanosine-diphosphate (GDP) bound form.

The weak intrinsic GTPase activity of RAS proteins is greatly enhanced by the action of GTPase-activating proteins (GAPs). GAP is an effector of RAS oncogene action.

Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins.

GTP binding can be catalyzed by guanine nucleotide exchange factors for RAS, and GTP hydrolysis can be accelerated by GTPase-activating proteins (GAPs).

Members

HRAS

KRAS

NRAS

Function

RAS genes encode membrane-bound guanine nucleotide-binding proteins that function in the transduction of signals that control cell growth and differentiation.

Binding of GTP activates RAS proteins, and subsequent hydrolysis of the bound GTP to GDP and phosphate inactivates signaling by these proteins.

GTP binding can be catalyzed by guanine nucleotide exchange factors for RAS, and GTP hydrolysis can be accelerated by GTPase-activating proteins (GAPs).

The first exchange factor to be identified for RAS was the S. cerevisiae CDC25 gene product. Genetic analysis indicated that CDC25 is essential for activation of RAS proteins. In Drosophila, the protein encoded by the ’son of sevenless’ gene (Sos) contains a domain that shows sequence similarity with the catalytic domain of CDC25. Sos may act as a positive regulator of RAS by promoting guanine nucleotide exchange.

Members

 RASs

• H-ras (HRAS) (MIM.190020)
• Ki-ras (KRAS) (MIM.190070)
• N-ras (NRAS) (MIM.164790)

 Rab (Rab GTPases)
 Rho
 Ral
 RAF

Function

The Ras family of small G proteins, which includes H-ras, R-ras and Rap, are important elements in cellular signalling pathways that control integrin function.

Pathology

It is well established that cancer is not caused by a mutation in a single gene, but requires genetic alterations affecting several pathways.

Ras genes are on their own insufficient to induce tumorigenesis but need cooperating oncogenes or inactivation of p53 or p16 in order to transform normal cells (Barbacid, 1987; Weinberg, 1989).

This is illustrated in neoplasms of the colon, where hyperplastic polyps, which only rarely progress to cancer, frequently have mutations of KRAS.

In contrast, dysplastic polyps that carry a high risk of progression first acquire mutations of APC, which are then followed by KRAS mutations (Jen et al., 1994).

These findings indicate that not only the type of genes whose functions are altered is important, but also the order in which these alterations occur.

For example, the HRAS activation in Spitz nevi may be analogous to the KRAS activation in hyperplastic polyps. It could result in incompletely transformed melanocytes that share several features with melanoma cells but have a limited proliferative capacity.

Links

 Animation of the organisation and function of the Ras-Raf-MEK-ERK pathway at Expert Reviews in Molecular Medicine

See also

 SOSs: SOS1

References

 Regulating the regulator: post-translational modification of RAS.
Ahearn IM, Haigis K, Bar-Sagi D, Philips MR. Nat Rev Mol Cell Biol. 2011 Dec 22;13(1):39-51. PMID: 22189424 [PubMed - in process]

 Parton RG, Hancock JF. Lipid rafts and plasma membrane microorganization: insights from Ras. Trends Cell Biol. 2004 Mar;14(3):141-7. PMID: 15003623

 Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003 Jun;3(6):459-65. PMID: 12778136

 Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. Understanding Ras: ’it ain’t over ’til it’s over’. Trends Cell Biol. 2000 Apr;10(4):147-54. PMID: 10740269