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; 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 nucleotide- exchange factor (GEF) and inactivated by a GTPase- activating protein (GAP).

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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

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 About 12 million contracted malignant tumors in RAS is responsible for about 20% of all human tumors. By learning about K-RAS we can learn about other pathways related to cancer.