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This question pertains to the KRAS wikipedia page, and I just want to double check and clarify my own understanding of how this mutation works in cancer.

It states:

K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules.

So if K-Ras is a switch, does that mean that when there is K-Ras mutation, it functions defectively so that it does not shut off? So for example when it binds to GTP and converts it to GDP, KRAS does not shut off regardless of GTP is converted to GDP and this would lead to / cause cancer.

So I guess I have several questions to my reasoning above..

  1. Why does excess conversion of GTP to GDP lead to cancer? Is it because this is specifically pertaining to the the RAS pathway?

  2. When I referenced above "it" is the K-Ras binding event the K-Ras protein binding to GTP then converting to GDP caused by the K-RAS gene not being able to function correctly? I'm just confused if its the K-Ras gene causing the problem or the K-Ras protein being the problem, or is it both?

  3. If K-Ras acts as a molecular switch, how to GEFs/GAPs effect K-Ras mutations? Because I know GEFS activate the conversion of of GTP to GDP, but what is its relationship to KRAS/K-Ras?

In the next line it states:

When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

  1. Is this saying when K-Ras is bound to GDP, that the conversion of GTP to GDP won't ever stop? I kind of just don't understand why this was written or what its relevance is. Or is it simply stating K-Ras can only turn on GTP to convert it in to GDP but not the other way around?
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NRAS is indeed a molecular switch, as part of the MAP-Kinase signaltransduction pathway it acts in controling the signal which goes downstream and finally will cause the expression of genes. In the case of NRAS this includes genes for proliferation, which is important for tumors. In principle, this looks like shown on this figure (from here):

enter image description here

RAS (this is the same for all three RAS family members) needs to be activated so it can signal downstream, this happens, when GTP is bound to the protein. Since permanent activation is obviously not a good idea, RAS itself has an intrinsic, but slow GTPase activity, which is activated by GTPase-activating proteins (GAP) and will eventually cleave the terminal phosphate group group from the GTP to make GDP + P. GDP bound RAS is inactive. GDP stays bound to the RAS protein and needs to be exchanged against GTP by Nucleotide Exchange factors (NEF) to activate RAS again.

The general principle is shown in this figure (from here):

enter image description here

Mutations in RAS proteins occur in 98% of the time in three locations (see reference 1): In codons 12, 13 and 61. All three mutation affect the ability of the protein to break down GTP by abolishing the intrinsic GTPase activity by the GAP (see reference 2). This leads to the accumulation of RAS protein which is permanently bound to GTP and therefore activated, subsequently activation transcription of genes for proliferation (amongst others). This process can lead to the formation of cancer.

Your questions:

  1. The conversation of GTP to GDP does not lead to cancer. This process stops the activation of RAS proteins. It is the permanent activation which causes the problems.

  2. You have the mutation in the KRAS gene, which is the origin of the problem. The wrong activation is of course done by the KRAS protein.

  3. GEFs facilitate the exchange of GDP to GTP, the break down of GTP is supported by the GAPs. The mutation hinders the GAP to fulfill their role, so they are useless in the mutated form of the protein.

  4. The other way round. If RAS proteins are bound to GDP, they are rendered inactive, unless a GEF exchanges it again to GTP.

References:

  1. RAS isoforms and mutations in cancer at a glance
  2. Guanosine triphosphatase activating protein (GAP) interacts with the p21 ras effector binding domain.
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