KRAS

KRAS is a gene encoding the KRas proto-oncogene. Like other members of the Ras gene family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways and is usually associated with cell membranes due to the presence of an isoprenyl group on its c-terminus.

KRAS acts as a molecular on/off switch, once it is turned on it recruits and activates proteins necessary for the propagation of growth factor and other receptors' signal, such as c-Raf and PI 3-kinase. KRAS binds to GTP in the active state and possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide converting it to GDP. Upon conversion of GTP to GDP, KRAS is turned off. The rate of conversion is usually slow but can be sped up dramatically by an accessory protein of the GTPase activating protein (GAP) class, for example RasGAP. In turn KRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example SOS1, which forces the release of bound nucleotide. Subsequently, the unbound HRAS is released from the GEF and quickly re-binds available GTP or GDP present in the cytosol. Since GTP is substantially more abundant than GDP, this usually results in HRAS activation.

Other members of the Ras family include: HRAS, RRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell.

Genetic Disease Associated with KRAS

Several germline KRAS mutations have been found to be associated with Noonan syndrome [cite journal |author=Schubbert S, Zenker M, Rowe SL, "et al" |title=Germline KRAS mutations cause Noonan syndrome |journal=Nat. Genet. |volume=38 |issue=3 |pages=331–6 |year=2006 |pmid=16474405 |doi=10.1038/ng1748 and cardio-facio-cutaneous syndrome [cite journal |author=Niihori T, Aoki Y, Narumi Y, "et al" |title=Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome |journal=Nat. Genet. |volume=38 |issue=3 |pages=294–6 |year=2006 |pmid=16474404 |doi=10.1038/ng1749.

Somatic Diseases Associated with KRAS

Somatic KRAS mutations are found at high rates in Leukemias, colon cancer [cite journal |author=Burmer GC, Loeb LA |title=Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue=7 |pages=2403–7 |year=1989 |pmid=2648401 |doi=, pancreatic cancer [cite journal |author=Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M |title=Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes |journal=Cell |volume=53 |issue=4 |pages=549–54 |year=1988 |pmid=2453289 |doi=10.1016/0092-8674(88)90571-5 and lung cancer [cite journal |author=Tam IY, Chung LP, Suen WS, "et al" |title=Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features |journal=Clin. Cancer Res. |volume=12 |issue=5 |pages=1647–53 |year=2006 |pmid=16533793 |doi=10.1158/1078-0432.CCR-05-1981] .KRAS mutation is predictive of response to cetuximab therapy in colorectal cancer [cite journal |author=Lièvre A, Bachet JB, Le Corre D, "et al" |title=KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer |journal=Cancer Res. |volume=66 |issue=8 |pages=3992–5 |year=2006 |pmid=16618717 |doi=10.1158/0008-5472.CAN-06-0191] . According to this reference whatever the expression of EGFR, KRAS mutation is associated with activation of the Ras/MAPK pathway. KRAS mutations can induce non-response [cite web |url=http://www.healthvalue.net/egfreceptor.html |title=EGF receptor |accessdate=2007-11-05] to anti-EGFR monoclonals (panitumumab, cetuximab), or EGFR-TK inhibitors (erlotinib, gefitinib).

KRAS Testing

KRAS mutational analysis is commercially available from a number of laboratories.

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Kahn S, Yamamoto F, Almoguera C, "et al." |title=The c-K-ras gene and human cancer (review). |journal=Anticancer Res. |volume=7 |issue= 4A |pages= 639–52 |year= 1987 |pmid= 3310850 |doi=
*cite journal | author=Yamamoto F, Nakano H, Neville C, Perucho M |title=Structure and mechanisms of activation of c-K-ras oncogenes in human lung cancer. |journal=Prog. Med. Virol. |volume=32 |issue= |pages= 101–14 |year= 1985 |pmid= 3895297 |doi=
*cite journal | author=Porta M, Ayude D, Alguacil J, Jariod M |title=Exploring environmental causes of altered ras effects: fragmentation plus integration? |journal=Mol. Carcinog. |volume=36 |issue= 2 |pages= 45–52 |year= 2003 |pmid= 12557259 |doi= 10.1002/mc.10093
*cite journal | author=Smakman N, Borel Rinkes IH, Voest EE, Kranenburg O |title=Control of colorectal metastasis formation by K-Ras. |journal=Biochim. Biophys. Acta |volume=1756 |issue= 2 |pages= 103–14 |year= 2006 |pmid= 16098678 |doi= 10.1016/j.bbcan.2005.07.001
*cite journal | author=Castagnola P, Giaretti W |title=Mutant KRAS, chromosomal instability and prognosis in colorectal cancer. |journal=Biochim. Biophys. Acta |volume=1756 |issue= 2 |pages= 115–25 |year= 2006 |pmid= 16112461 |doi= 10.1016/j.bbcan.2005.06.003
*cite journal | author=Deramaudt T, Rustgi AK |title=Mutant KRAS in the initiation of pancreatic cancer. |journal=Biochim. Biophys. Acta |volume=1756 |issue= 2 |pages= 97–101 |year= 2006 |pmid= 16169155 |doi= 10.1016/j.bbcan.2005.08.003
*cite journal | author=Pretlow TP, Pretlow TG |title=Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer? |journal=Biochim. Biophys. Acta |volume=1756 |issue= 2 |pages= 83–96 |year= 2006 |pmid= 16219426 |doi= 10.1016/j.bbcan.2005.06.002
*cite journal | author=Su YH, Wang M, Aiamkitsumrit B, "et al." |title=Detection of a K-ras mutation in urine of patients with colorectal cancer. |journal=Cancer biomarkers : section A of Disease markers |volume=1 |issue= 2-3 |pages= 177–82 |year= 2007 |pmid= 17192038 |doi=

External links

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