Introduction to Signal Transduction and Cancer:
A cell of our body depends upon the signal transduction pathway to carry out different types of cell processes at the right moment in time to basically produce physiological responses to certain types of external stimuli.
Now, even though signal transduction is very important to the functionality of our cell. These signal transduction pathways must be closely maintained and regulated by our cells.
In fact, the inability of our cell to regulate and terminate these signal transduction pathways can actually lead to tumor growth and eventually cancer.
Epidermal growth factor (EGF) signal transduction pathway is the pathway used by the cell that ultimately stimulates cell growth and division of epithelial and epidermal cells.
Two EGF molecules bind onto each one of the domains of EGF receptors, once the binding takes place these monomers associate one another to form a dimer and induce conformational changes in the structure found in the cytoplasm.
The domain in the cytoplasm part contains tyrosine kinase domains. When a conformational change takes place upon binding and dimerization process a cross phosphorylation takes place and the carboxy terminal ends of the receptor are phosphorylated by the active site of the corresponding kinase. Once the phosphorylation residues, the very important adapter protein GRB2 (Growth Factor Receptor-Bound Protein 2) binds to the C-terminal that calls upon another protein known as SOS. SOS binds inactive small G-proteins known as Ras.
When Ras binds to SOS protein, there is a conformational change that takes place in the Ras protein and GDP is expelled and GTP is moved into the pocket. Once GTP binds it will activate the G-protein known as Ras, when Ras is activated, it will also activate a protein kinase Raf. Once this protein kinase is activated, it will activate the other protein kinase known as MEK (mitogen-activated protein kinase. The MEK once activated, it will activate another kinase protein ERK (Extracellular Signal-Regulated Kinase). Now, these ERKs can actually move into the nucleus of the cell through the double phospholipid bilayer of the nucleus. These ERKS go into the cell nucleus and activate transcription factors. These transcription factors will express several types of gene that will eventually produce mRNA molecules which then become axes of the cell and are essentially used by the ribosomes to synthesize proteins.
The proteins are in turn used to build cytoplasm and cytoskeleton which increase the size of the cell and eventually are able to divide.
So, in this process EGF signal transduction pathway stimulates cell differentiation, cell growth and cell proliferation in two types of cells including epithelial and epidermal cells.
Regulation and Termination of EGF Pathway:
Now, once this pathway is carried out, there are several mechanisms for how this pathway will be terminated in a normal cell. Basically, there are three major methods
By using GTPase activity of the G Proteins
Because it has a G-protein involved and it has GTPase activity, i.e., they have a built-in-clock that allows it to actually shut itself down following activation.
So, sometime after this has been activated into the GTP form, the GTPase activity takes water molecules from the cytoplasm and hydrolyzes the GTP back to GDP and once it is inactivated there longer can stimulate the rest of the process. So, the pathway will shut down as a result. So, the cell can terminate by using GTPase activity of G-protein.
By using phosphatases to reverse the effect of protein kinase
The cell can also actually terminate the pathway by using a class of molecule known as phosphatase. So, in fact, as soon as this pathway is activated, it will also activate many different types of phosphatases that remove the phosphate group that were attached by protein kinase. For instance, the Raf, MEK, ERK and the C-terminal of the EGF receptor acts as a protein kinase in this particular case. Basically, phosphatases move on the target protein and they will remove the phosphate group that were placed by all these different types of protein kinases. Therefore, phosphatase will remove the phosphate groups and that essentially inactivate this pathway and eventually the pathway can’t be continued and result in shut down.
By inactivating the receptor of the pathway
If the two ligands dissociate and when the ligands dissociate these two entire dimers basically break apart into monomers and in those particular cases it is not active. So, it will decrease the activity of this signal transduction pathway.
Cancer Development Due to Signaling Malfunction:
- One way by which signal transduction pathways may malfunction is if a gene coding for a protein part of the pathway is mutated.The Ras gene code for Ras protein in the EGF pathway is the most commonly mutated gene that leads to the growth of the epithelial cells. A mutation in the gene might produce a Ras protein that ATpase activity, which means it cannot turn itself off. Therefore, the stimulation of cells. Such a gene is called an oncogene.
- Phosphatase are tumor suppressing molecules because they are inactive proteins and enzymes that drive signal transduction pathways. For this reason, we call genes that code for phosphatases tumor suppressing genes.When both genes in the allele pair encoding for phosphatases are knocked out, that may lead to tumor formation because the cell will not be able to terminate the signal transduction pathway.
- Overexpression of tyrosine kinase receptors can also lead to cancer of epithelial cells (i.e., breast, ovarian, rectal). If a cell expresses too many receptors, the excess receptor may stimulate growth at inappropriate times. Drugs (antibodies) have been developed that can bind to these overexpressed receptors, thereby deactivating their activity. Receptin is one such drug that targets tyrosine kinase receptors called Her2 that are over expressed in many cancer patients.