Oncogenes and Cell Signalling

The Ras protein occupies a central role in directing extracellular signals to the nucleus, where specific genes are activated for cell growth, division, and differentiation. Ras-related proteins have been discovered in such diverse organisms as yeast, nematode worms, and Drosophila, in which they control aspects of mitotic and meiotic growth and embryonic development. Research on these organisms has illuminated a central control pathway in mammalian cells (Figure 23.23), in the process richly justifying the use of simple biological model systems for cancer research.

Many growth factor receptors with tyrosine kinase activity phosphorylate themselves (steps 1 and 2 in Figure 23.23). In the phosphorylated state, each receptor interacts with one or more protein exchange factors, which in turn activate Ras by stimulating the GDP-GTP exchange (step 3). Also interacting with Ras, and limiting its activity, are proteins called GAPs (GTPase-activating proteins). Ras activates a cascade of further protein phosphorylations (step 4), which ultimately activates transcription factors (step 5). These factors interact with the genome and stimulate the expression of particular genes (see here and here).

As noted in Figure 23.23, one class of downstream kinases is called MAP kinase (MAPK). The acronym MAP stands for mitogen-activated protein. (A mitogen is a factor that stimulates mitosis.) Upstream of MAP kinases are another family of proteins, MAPKK (MAP kinase kinase), and still further upstream are the MAPKKK proteins (MAP kinase kinase kinase). One member of MAPKKK class of proteins is the product of the raf proto-oncogene (see Table 23.7). Mammalian cells contain seven known MAPKKKs, seven MAPKKs, and six MAPKs.

Thus, growth factor response is a cascade of protein phosphorylations, analogous to the cascade that controls glycogen breakdown. Blocking the Ras GTPase activity can lead to uncontrolled cell growth and cancer, by keeping the signalling pathway turned on and flooding the cell with growth-stimulatory signals. It is not yet clear how this pathway can explain the distinct responses of cells to different growth factors.

See also: Viral and Cellular Oncogenes, Oncogenes in Human Tumors, G Proteins and Signal Transduction, G Protein Families and Subunits, Receptors with Protein Kinase Activity, Hormone Action