Question

A single amino acid change in Ras eliminates its ability to hydrolyze GTP even in the presence of a GTPase-activating protein (GAP). Roughly 30% of human cancers have this change in Ras. You have just identified a small molecule that prevents the dimerization of a receptor tyrosine kinase that signals via Ras. Would you expect this molecule to be effective in the treatment of cancers that express this common, mutant form of Ras? Why or why not?

(Please give me a proper detailed explaination)

Answer 1

Ans- No,

Ras acts as a typical molecular switch. The GTP-bound Ras can activate several downstream effector pathways. Ras signaling regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc.

When Ras function is not properly regulated, hyper-proliferation can occur resulting in developmental disorders and cancer.

Ras pathway works as- Binding of growth factors to receptor tyrosine kinases stimulates the autophosphorylation of specific tyrosines on the receptors. The phosphorylated receptor then binds to an adaptor protein called GRB2 which, in turn, recuits SOS to the plasma membrane. SOS is a guanine nucleotide exchange factor which displaces GDP from Ras, subsequently allowing the binding of GTP.  GTP-bound Ras recruits and activates Raf. Raf initates a cascade of protein phosphorylation by first phophorylating MEK. Phosphorylated MEK in turn phosphorylates ERK. Phosphorylated ERK moves from the cytoplasm into the nucleus where it subsequently phosphorylates a number of transcription factors, including the specific transcription factor called Elk-1. Phosphorylated transcription factors turn on transcription (gene expression) of specific sets of target genes.

The activity of Ras is limited by the hydrolysis of GTP back to GDP by GTPase activating proteins. So, if the mutation, eliminates its ability to hydrolyze GTP even in the presence of a GTPase-activating protein (GAP), leads to  favor constitutive activation of Ras, meaning that the gene is always “turned on,” and there is overproduction of the protein. The mutation also increases GTP binding, leading to overactivity.further activation signaling by an RTK would not be effective in treating this cancer.

Targeted drug design for prevention of cancer by this mutation could be envisaged in mainly four ways, such as prevention of Ras-GTP formation, covalent locking of the GDP-bound Ras, inhibition of Ras-effector interactions, or impairment of post-translational modification of Ras.