2-6-3. Propagation of the Signal
Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. Continuation of a signal in this manner is called
When a ligand binds to its receptor, conformational changes occur that affect the receptor’s intracellular domain. Conformational changes of the extracellular domain upon ligand binding can propagate through the membrane region of the receptor and lead to activation of the intracellular domain or its associated proteins. In some cases, binding of the ligand causes
Binding Initiates a Signaling Pathway
After the ligand binds to the cell-surface receptor, the activation of the receptor’s intracellular components sets off a chain of events that is called a
In certain cancers, the GTPase activity of the RAS G-protein is inhibited. This means that the RAS protein can no longer hydrolyze GTP into GDP. What effect would this have on downstream cellular events?
Signaling pathways can get very complicated very quickly because most cellular proteins can affect different downstream events, depending on the conditions within the cell. A single pathway can branch off toward different endpoints based on the interplay between two or more signaling pathways, and the same ligands are often used to initiate different signals in different cell types. This variation in response is due to differences in protein expression in different cell types. Another complicating element is
The effects of extracellular signals can also be amplified by enzymatic cascades. At the initiation of the signal, a single ligand binds to a single receptor. However, activation of a receptor-linked enzyme can activate many copies of a component of the signaling cascade, which amplifies the signal.
Methods of Intracellular Signaling
The induction of a signaling pathway depends on the modification of a cellular component by an enzyme. There are numerous enzymatic modifications that can occur, and they are recognized in turn by the next component downstream. The following are some of the more common events in intracellular signaling.
Link to Learning
Observe an animation of cell signaling at this site.
One of the most common chemical modifications that occurs in signaling pathways is the addition of a phosphate group (PO4–3) to a molecule such as a protein in a process called phosphorylation. The phosphate can be added to a nucleotide such as GMP to form GDP or GTP. Phosphates are also often added to serine, threonine, and tyrosine residues of proteins, where they replace the hydroxyl group of the amino acid (Figure 2). The transfer of the phosphate is catalyzed by an enzyme called a
Calcium ion is a widely used second messenger. The free concentration of calcium ions (Ca2+) within a cell is very low because ion pumps in the plasma membrane continuously use adenosine-5'-triphosphate (ATP) to remove it. For signaling purposes, Ca2+ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca2+. The response to the increase in Ca2+ varies, depending on the cell type involved. For example, in the β-cells of the pancreas, Ca2+ signaling leads to the release of insulin, and in muscle cells, an increase in Ca2+ leads to muscle contractions.
Another second messenger utilized in many different cell types is
Present in small concentrations in the plasma membrane,
The enzyme phospholipase C cleaves PIP2 to form
Ligand binding to the receptor allows for signal transduction through the cell. The chain of events that conveys the signal through the cell is called a signaling pathway or cascade. Signaling pathways are often very complex because of the interplay between different proteins. A major component of cell signaling cascades is the phosphorylation of molecules by enzymes known as kinases. Phosphorylation adds a phosphate group to serine, threonine, and tyrosine residues in a protein, changing their shapes, and activating or inactivating the protein. Small molecules like nucleotides can also be phosphorylated. Second messengers are small, non-protein molecules that are used to transmit a signal within a cell. Some examples of second messengers are calcium ions (Ca2+), cyclic AMP (cAMP), diacylglycerol (DAG), and inositol triphosphate (IP3).
Figure 1. In certain cancers, the GTPase activity of the RAS G-protein is inhibited. This means that the RAS protein can no longer hydrolyze GTP into GDP. What effect would this have on downstream cellular events?
Figure 1. ERK would become permanently activated, resulting in cell proliferation, migration, adhesion, and the growth of new blood vessels. Apoptosis would be inhibited.
Where do DAG and IP3 originate?
What property enables the residues of the amino acids serine, threonine, and tyrosine to be phosphorylated?
The same second messengers are used in many different cells, but the response to second messengers is different in each cell. How is this possible?
Different cells produce different proteins, including cell-surface receptors and signaling pathway components. Therefore, they respond to different ligands, and the second messengers activate different pathways. Signal integration can also change the end result of signaling.
What would happen if the intracellular domain of a cell-surface receptor was switched with the domain from another receptor?
The binding of the ligand to the extracellular domain would activate the pathway normally activated by the receptor donating the intracellular domain.
cyclic AMP (cAMP)
cyclic AMP-dependent kinase
inositol triphosphate (IP3)