Ras

This article is about the Ras family of proteins. For other meanings see the Ras (disambiguation) page.

Complex of Rho GDP-dissociation inhibitor 2 (yellow) with G-protein RAC2 (red)

Identifiers
Symbol| Ras
Pfam| PF00071
InterPro| IPR013753
PROSITE| PDOC00859
SCOP| 5p21
SUPERFAMILY| 5p21
OPM protein| 1uad
| Available protein structures:

Pfam| structures
PDB| RCSB PDB; PDBe; PDBj
PDBsum| structure summary

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

## Overview

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In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. The Ras superfamily of small GTPases includes the Ras, Rho, Arf, Rab, and Ran families.

## History

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Ras gene was the first human oncogene discovered by Robert A. Weinberg of MIT in early 80's from a bladder cancer cell line.[1]

## Functions

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Proteins in the Ras family are very important molecular switches for a wide variety of signal pathways that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis, and cell migration.

Ras and ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis.

RAS activates a number of pathways but an especially important one seems to be the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins.[2]

## Activated and inactivated forms

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RAS is a G protein (specifically a small GTPase): a regulatory GTP hydrolase that cycles between two conformations - an activated or inactivated form, respectively RAS-GTP and RAS-GDP.

It is activated by guanine exchange factors (GEFs, eg. CDC25, SOS1 and SOS2, SDC25 in yeast), which are themselves activated by mitogenic signals and through feedback from Ras itself. A GEF usually heightens the dissociation rate of the nucleotide - while not changing the association rate (effectively lower the affinity of the nucleotide) - thereby promoting its exchange. The cellular concentration of GTP is much higher than that of GDP so the exchange is usually GDP vs. GTP.

It is inactivated by GTPase-activating proteins (GAPs, the most frequently cited one being RasGAP), which increase the rate of GTP hydrolysis, returning RAS to its GDP-bound form, simultaneously releasing an inorganic phosphate.

## Attachments

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Ras is attached to the cell membrane by prenylation, and in health is a key component in many pathways which couple growth factor receptors to downstream mitogenic effectors involved in cell proliferation or differentiation.[3] The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol and then inserted into the membrane of the endoplasmatic reticulum. The Tripeptid (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease, the new C-terminus is the methylated by a methyltransferase. The so processed Ras is now transported to the plasma membrane. Most Ras forms are now further palmityolated, while K-Ras with its long positively charged stretch interacts electrostaticly with the membrane.

## Ras in cancer

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Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.[4]

### Inappropriate activation of the gene

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Inappropriate activation of the gene has been shown to play a key role in signal transduction, proliferation and malignant transformation.[2]

Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively activated their signals will transduce through Ras.

The tumour suppressor gene NF1 encodes a Ras-GAP - its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated. Ras can also be amplified, although this only occurs occasionally in tumours.

Finally, Ras oncogenes can be activated by point mutations so that its GTPase reaction can no longer be stimulated by GAP - this increases the half life of active Ras-GTP mutants.[3]

### Constitutively active Ras

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Constitutively active Ras (RasD) is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state.

The most common mutations are found at residue G12 in the P-loop and the catalytic residue Q61.

* The glycine to valine mutation at residue 12 renders the GTPase domain of Ras insensitive to activation by GAP and thus stuck in the "on state". Ras requires a GAP for inactivation as it is a relatively poor catalyst on its own, as opposed to other G-domain-containing proteins such as the alpha subunit of heterotrimeric G proteins.

* Residue 61[5] is responsible for stabilizing the transition state for GTP hydrolysis. Because enzyme catalysis in general is achieved by lowering the energy barrier between substrate and product, mutation of Q61 necessarily reduces the rate of intrinsic Ras GTP hydrolysis to physiologically meaningless levels.

See also "dominant negative" mutants such as S17N and D119N.

## Human proteins containing Ras domain

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ARHE; ARHGAP5; CDC42; DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; GRLF1; HRAS; KRAS; LOC393004; MRAS; NKIRAS1; NRAS; RAB10; RAB11A; RAB11B; RAB12; RAB13; RAB14; RAB15; RAB17; RAB18; RAB19; RAB1A; RAB1B; RAB2; RAB20; RAB21; RAB22A; RAB23; RAB24; RAB25; RAB26; RAB27A; RAB27B; RAB28; RAB2B; RAB30; RAB31; RAB32; RAB33A; RAB33B; RAB34; RAB35; RAB36; RAB37; RAB38; RAB39; RAB39B; RAB3A; RAB3B; RAB3C; RAB3D; RAB40A; RAB40AL; RAB40B; RAB40C; RAB41; RAB42; RAB43; RAB4A; RAB4B; RAB5A; RAB5B; RAB5C; RAB6A; RAB6B; RAB6C; RAB7A; RAB7B; RAB7L1; RAB8A; RAB8B; RAB9; RAB9B; RABL2A; RABL2B; RABL4; RAC1; RAC2; RAC3; RALA; RALB; RAN; RANP1; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASEF; RASL11A; RASL12; RBJ; REM1; REM2; RERG; RHEB; RHEBL1; RHOA; RHOB; RHOBTB1; RHOBTB2; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RIT1; RIT2; RND1; RND2; RND3; RRAD; RRAS; RRAS2; TC4;

## References

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1. ↑ Shih, C. and Weinberg, R.A. (1982). "Isolation of a transforming sequence from a human bladder carcinoma cell line". Cell. 29: 161–169.CS1 maint: Multiple names: authors list (link)
2. ↑ 2.0 2.1 Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000). "Chapter 25, Cancer". Molecular cell biology (4th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-3706-X.CS1 maint: Multiple names: authors list (link)
3. ↑ 3.0 3.1 Reuter C, Morgan M, Bergmann L (2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?". Blood. 96 (5): 1655–69. PMID 10961860.CS1 maint: Multiple names: authors list (link)
4. ↑ Bos J (1989). "ras oncogenes in human cancer: a review". Cancer Res. 49 (17): 4682–9. PMID 2547513.
5. ↑ http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164790&a=164790_AllelicVariant0002

## External links

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* "Brain tumour findings offer hope of new strategy Canadian Cancer Society says" at ncic.cancer.ca
* "Novel cancer treatment gets NCI support" at arstechnica.com
* ras+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
* ras+Genes at the US National Library of Medicine Medical Subject Headings (MeSH)

* v
* t
* e

Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes

Ligand|

| Growth factors|

| ONCO|

* c-Sis/PDGF
* HGF

|

Receptor|

| Wnt signaling pathway|

| TSP|

* CDH1

|

Hedgehog signaling pathway|

| TSP|

* PTCH1

|

TGF beta signaling pathway|

| TSP|

* TGF beta receptor 2

|

Receptor tyrosine kinase|

| ONCO|

* ErbB/c-ErbB
* HER2/neu
* Her 3
* c-Met
* c-Ret

|

JAK-STAT signaling pathway|

| ONCO|

* c-Kit
* Flt3

|

Intracellular signaling P+Ps|

| Wnt signaling pathway|

| ONCO|

* Beta-catenin

|

TSP|

* APC

TGF beta signaling pathway|

| TSP|

* SMAD2
* SMAD4

|

Akt/PKB signaling pathway|

| ONCO|

* c-Akt

|

TSP|

* PTEN

Hippo signaling pathway|

| TSP|

* Neurofibromin 2/Merlin

|

MAPK/ERK pathway|

| ONCO|

* c-Ras
* HRAS
* c-Raf

|

TSP|

* Neurofibromin 1

Other/unknown|

| ONCO|

* c-Src

|

TSP|

* Maspin

Nucleus|

| Cell cycle|

| ONCO|

* CDK4
* Cyclin D
* Cyclin E

|

TSP|

* p53
* pRb
* WT1
* p16/p14arf

DNA repair/Fanconi|

| TSP|

* BRCA1
* BRCA2

|

Ubiquitin ligase|

| ONCO|

* CBL
* MDM2

|

TSP|

* VHL

Transcription factor|

| ONCO|

* AP-1
* c-Fos
* c-Jun
* c-Myc

|

TSP|

* KLF6

Mitochondrion|

| Apoptosis inhibitor|

* SDHB
* SDHD

|

Other/ungrouped|

* c-Bcl-2
* Notch
* Stathmin

* v
* t
* e

Hydrolases: acid anhydride hydrolases (EC 3.6)

3.6.1|

* Pyrophosphatase
* Inorganic
* Thiamine
* Apyrase
* Thiamine-triphosphatase

3.6.2|

* Adenylylsulfatase
* Phosphoadenylylsulfatase

3.6.3-4: ATPase|

| 3.6.3|

| Cu++ (3.6.3.4)|

* Menkes/ATP7A
* Wilson/ATP7B

|

Ca+ (3.6.3.8)|

* SERCA
* ATP2A1
* ATP2A2
* ATP2A3
* Plasma membrane
* ATP2B1
* ATP2B2
* ATP2B3
* ATP2B4
* SPCA
* ATP2C1
* ATP2C2

Na+/K+ (3.6.3.9)|

* ATP1A1
* ATP1A2
* ATP1A3
* ATP1A4
* ATP1B1
* ATP1B2
* ATP1B3
* ATP1B4

H+/K+ (3.6.3.10)|

* ATP4A

Other P-type ATPase|

* ATP8B1
* ATP10A
* ATP11B
* ATP12A
* ATP13A2
* ATP13A3

3.6.4|

* Dynein
* Kinesin
* Myosin
* Katanin

3.6.5: GTPase|

| 3.6.5.1: Heterotrimeric G protein|

* Gαs
* Gαi
* GNAI1
* GNAI2
* GNAI3
* Gαq/11
* GNAQ
* GNA11
* Gα12/13
* GNA12
* GNA13
* Transducin
* GNAT1
* GNAT2
* Gustducin
* GNAT3

|

3.6.5.2: Small GTPase > Ras superfamily|

* Rho family of GTPases: Cdc42
* CDC42
* TC10
* TCL
* RhoUV
* RhoU
* RhoV
* Rac
* Rac1
* 2
* 3
* RhoG
* RhoBTB
* 1
* 2
* RhoH
* Rho
* A
* B
* C
* Rnd
* 1
* 2
* 3
* RhoDF
* RhoF
* RhoD

* other: Ras
* HRAS
* KRAS
* NRAS
* Rab
* RAB23
* RAB27
* Arf
* ARF6
* SAR1B
* ARL13B
* ARL6
* Ran
* Rheb
* Rap
* RGK

3.6.5.3: Protein-synthesizing GTPase|

* Prokaryotic
* IF-2
* EF-Tu
* EF-G
* Eukaryotic

3.6.5.5-6: Polymerization motors|

* Dynamin
* Tubulin

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