Transcript K-RAS - Informatics: Indiana University

K-RAS
( Kirsten RAS )
Mira Han, Pedro Alves
What is K-RAS?
• A kind of guanine nucleotide (GTP/GDP)
binding protein with intrinsic GTPase
activity.
• Member of the RAS protein family.
• Size: 189 amino acids; 21656 Da
• Attached to the Internal side of plasma
membrane by a lipid anchor.
What does K-RAS do?
• 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
• Activated by a guanine nucleotideexchange factor (GEF) and inactivated by
a GTPase- activating protein (GAP).
MAPK signaling pathway
• http://www.reactome.org/cgibin/search?QUERY_CLASS=DatabaseIde
ntifier&QUERY=UniProt:P01116
• http://www.genome.ad.jp/dbgetbin/show_pathway?hsa04010+3845
• http://wwwermm.cbcu.cam.ac.uk/swf001wkg.swf
Oncogene Protein p21 (RAS)
• Transforming protein encoded by ras
oncogenes. Point mutations in the cellular
ras gene (c-ras) can also result in a
mutant p21 protein that can transform
mammalian cells. Oncogene protein
p21(ras) has been directly implicated in
human neoplasms, perhaps accounting for
as much as 15-20% of all human tumors.
EC 3.6.1.-.
Pathology related with KRAS
• germline KRAS mutations in
– Noonan syndrome
– cardio-facio-cutaneous syndrome
• somatic mutations
– in lung carcinoma
– in breast carcinoma
– in pancreatic carcinoma
– in gastric carcinoma
– in acute myeloblastic leukemia
Proto-oncogene
•Normal gene that can become an
oncogene throught
–Mutation, or
–Increased expression
•Oncogene is a gene that
increases the chance that a
normal cell develops into a tumor
cell
K-RAS
• K-RAS is the form (of RAS) found most
often mutated in cancer
• The mutant oncogene is hard to be
differentiated by drugs since most of the
times it only has one amino acid difference
Possible Treatment
• Blocking RAS isoprenylation
– Isoprenylation is the addition of hydrophobic
molecules to a protein to facilitate its
attachment to the cell membrane
Farnesyltransferase inhibitors
(FTI’s)
• Farnesyltransferase (FFTase)
– transferring a farnesyl group from farnesyl
pyrophosphate (FPP) to the pre-RAS protein
(isoprenylation)
• GGTase
• FTIs and GTIs was tried
– resulted in high toxicity
What was learned
• FFTase inhibitors had preclinical
successes
• Inhibition of farnesylation of a number of
other proteins
• FTIs, whilst not RAS specific, still have
potential for cancer therapy
Why K-RAS?
• 6.2 million people died from cancer 2000.
• About 12 million contracted malignant
tumors in 2000.
• RAS is responsible for about 20% of all
human tumors.
• By learning about K-RAS we can learn
about other pathways related to cancer.