Ras protein
The 'choreographer' of cell life- (Baylor)
I. Basic information
It is a signal transduction protein that regulates and controls intracellular signaling networks by converting signals from the cell membrane to the nucleus(Wikipedia). It is part of the Ras superfamily encompassing 8 other subfamilies in which all share the common G core providing GTPase activity(Wikipedia). Ras proteins control cell migration, proliferation, differentiation, cell adhesion, and apoptosis(Wikipedia).
II. How Ras works
The protein is associated with the plasma membrane where it binds to either GDP or GTP acting as a molecular switch(Tufts University). When Ras is GDP bound, it is in the inactive state or the off position (Tufts University). It is activated by guanine nucleotide exchange factors (GEF) at the plamsa membrane that take the GDP off and replace it with a GTP (Pathfinder ; webhost). When it is GTP bound, Ras is active and able to activate other proteins(Tufts University). The protein itself has a natural inability to return from its active form back to its inactive form and it requires the help of the GTPase-activating protein or GAP (Tufts University).
This figure shows the on and off states for Ras. For a bigger image: (et al. biologie)
Ras and Signal Pathways
One single Ras protein can be involed in multiple signal pathways and regulate completely different functions. The question researchers wish to answer is how one protein regulates multpile factors and knows which process to activate(Chang). This is leading to theories that Ras is involved with compartment specific signaling (Chang).
An example of Ras in a pathway results in the transcription of genes involved in cell growth and division in which the mitogen-activated protein (MAP) kinase cascade has been well-studied. (Wikipedia-protein)
Ras in a general transduction pathway:
http://porpax.bio.miami.edu/~cmallery/150/gene/c7.19.12a.Ras.jpg
III. Mutations in Ras
There are 3 similar Ras proteins, present in mammalian speices, that are consider to be oncogenic (ncbi/rasoncogenes). Oncogenes are genes that when mutated help to turn a normal cell into a canerous cell (Wikipedia-oncogenes). Ras, when it was originally found, was thought to be the oncogene resonsible for the cancer-causing activity in the Harvey and Kirsten murine sarcoma viruses (Der Lab). It was then found that a mutation in the normal protein produces its oncogenic form (Singer). The Ras proteins that mostly undergo mutations are (ncbi/rasoncogenes):
K-Ras- This protein mutates most often and the mutations mostly occur in pancreatic and colon cancers.
N-Ras- Mutations mostly prevalent in melanoma, liver cancer, and luekemia.
H-Ras- Mutations occur in bladder, kidney, and thyroid carcinomas
Mutations in the ras genes can permanently activate the protein resulting in incorrect signaling inside the cell(ncbi/rasoncogenes). Pancreatic cancer has been highly linked to Ras protein mutations in which 90% of pancreatic tumors contain a mutation in the K-ras gene(ncbi/rasoncogenes ; cancer research). Colon cancer has also been highly linked in which 50% of colon tumors have an Ras mutation(ncbi/rasoncogenes). Even though K-Ras is the type most commonly mutated in colon cancer, not all colon tumors have a mutation in K-Ras. RASAL1, an Ras regulator, has also been found to be linked to tumor progression (RASAL1).
IV. Cancer Therapy
Since there is a high correlation between certain types of cancer and the Ras mutation, cancer therapy has been focused on developing anti-cancer drugs to act on the Ras protein (Oxford Journals). Three major approaches have been taken:
1) Inhibition of Ras Expression
2) Inhibition of Ras Membrane Localization
3) Interruption of Signaling Pathways downstream of Ras(Oxford Journals).