A growth factor can trigger a cell to grow, differentiate, or divide. Many growth factors act by binding to a receptor on the cell's surface, causing the receptor to initiate a series of events inside the cell that lead to a cellular response, such as cell division. The sequence of molecular events and chemical reactions that lead to a cell's response is called a signal transduction pathway.
Signal transduction pathways are by necessity highly regulated. If a pathway triggered by a growth factor cannot turn off, for example, cells may continually divide without regulation—that is, become cancerous. In this animation we look at the events of one type of signal transduction pathway, as well as how a mutant protein (called ras) in the cascade can result in cancer.
A signal transduction pathway is a sequence of molecular events and chemical reactions that lead to a cell's response to a signal. This example of a pathway begins with the binding of a growth factor to a protein kinase receptor. The binding unites the two parts of the receptor, which then rearranges to expose protein kinase active sites on the receptor's cytoplasmic domains. The receptor then phosphorylates itself. These initial actions based on growth factor binding will culminate in the cell taking a particular action, such as cell division.
In the first steps of the pathway, the activated receptor initiates a series of events that allow a small G protein called ras to become activated. G proteins are a family of guanine-nucleotide binding proteins. Ras, like other G proteins, functions as a binary switch.
In its inactive state, ras is bound to GDP. When ras is stimulated, it releases its GDP and takes up GTP. When bound to GTP, ras is active and can activate other proteins, resulting in a brief stimulation of cell division. An important part of ras's function is an internal shut-off mechanism. Shortly after becoming activated, ras hydrolyzes its GTP back to GDP, and in so doing becomes inactive again and stops stimulating cell division.
Some human cancers contain an abnormal form of ras. Investigations of these cancers showed that if the abnormal form of ras is stimulated to pick up GTP, it becomes permanently bound to GTP, because it cannot hydrolyze GTP into GDP and inorganic phosphate. Therefore, ras remains permanently activated and causes continuous cell division. If the abnormal form of ras is inhibited in some way, the cells stop dividing. This discovery has led to a major effort to develop specific ras inhibitors for cancer treatment.
Let's return to the normal form of ras. After it becomes activated, it activates a protein kinase called raf. Raf is the first in a series of protein kinases that become sequentially activated. The protein kinase cascade continues when raf phosphorylates and thereby activates MEK. MEK now phosphorylates and activates a protein kinase called MAP kinase.
At each step in the cascade of events, the signal is amplified, because each newly activated protein kinase is an enzyme that can catalyze the phosphorylation of many target proteins. The phosphorylated form of MAP kinase can enter the nucleus and initiate a cellular response, such as cell division.
In the accompanying animation, we look at one type of signal transduction pathway. It begins with the binding of a growth factor to a protein kinase receptor. The activated receptor initiates a series of events that leads to the activation of the protein ras, which in turn activates a protein kinase cascade, which ultimately results in a cellular response to the growth hormone.
Each activated member of the pathway must soon turn off to prevent abnormal cellular responses, such as uncontrolled cell division. Ras has a shut-off mechanism—it cleaves its bound GTP to form GDP, and thereby becomes inactive. Additionally, phosphatase enzymes turn off the protein kinases in the pathway by removing their activating phosphate groups.
About 20% of all tumors have an activating mutation in a ras gene (and a number of other cancers have abnormalities in other aspects of signal transduction). Investigations have shown that such abnormal forms of ras are always active because they are permanently bound to GTP, and thus cause continuous cell division. If the abnormal form of ras is inhibited, cells stop dividing. A major effort is underway to develop specific ras inhibitors for cancer treatment.