20.9 : The Ras Gene

Eukaryotic cells employ numerous intracellular and extracellular signaling cascades to respond appropriately to the external stimuli as well as to maintain their normal physiological functions.

These signaling cascades are controlled by a diverse set of intracellular regulatory proteins, such as the Ras proteins. 

Ras is a family of GTPases involved in the regulation of signaling pathways that control cell growth and proliferation.

These proteins are anchored to the cytoplasmic side of the plasma membrane, and transit between two states - the GTP bound active state, and the GDP bound inactive state.

In a healthy cell, an appropriate signaling molecule activates the tyrosine kinase receptor present on the cell surface.

The active receptor helps to recruit adapter proteins and Ras guanine nucleotide exchange factors or Ras GEFs, which act as a link between the receptor and the Ras protein.

The Ras GEFs then replace the GDP bound to the inactive RAS protein with a GTP, switching it into an active state.

The active Ras protein then further transmits the signal via a signaling cascade to activate the mitogen-activated protein kinase or MAP kinase.

The active MAP kinase phosphorylates transcription factors that turn on the genes encoding growth-promoting proteins and facilitate controlled cell growth and division.

However, Ras is a proto-oncogene that, upon hyperactivation can lead to uncontrolled proliferation of cells.

In normal situations, the cell employs special proteins called Ras GTPase-activating proteins or GAPs that can hydrolyze the GTP bound to the active Ras and transform it back to the inactive state.

But in the case of a Ras mutation, the altered protein may not allow Ras GAPs to hydrolyze the GTP.

This effectively turns RAS into a hyperactive protein which is constitutively active, even in the absence of external stimuli, and continuously transmits growth signals to the downstream signaling molecules. The result is uncontrolled cell growth and proliferation.

Mutations in the Ras genes have implications in many human cancers, especially colorectal cancer.