Cell Signaling V: Integration of multiple signals

Cell Signaling V:
Integration of Multiple Signals

I want to conclude this discussion of cell signaling by returning to a topic I've touched on previously--namely, the ways in which cell signaling molecules can interact with one another to augment or inhibit different pathways in the cell. There are a large diversity of ways in which this can occur, and I only want to briefly mention a few.
First of all, it is possible for the same receptor to interact with different "effector" molecules in cells. That is, an activated receptor might interact with a different effector system in one cell type than another. The example the book gives is EGF receptor, which is a receptor tyrosine kinase that usually activates a Ras/MAP kinase pathway, but can in some cells activate the PIP2 pathway by binding to Phospholipase C directly. The different cells presumably respond differently depending on whether EGF activates a MAP kinase or Protein kinase C. In addition, insulin can activate the Ras/MAP kinase pathway as well as a second messenger pathway involving protein kinase B (PKB), which is activated by binding to a phosphatidyl inositol phosphate in the plasma membrane (See Fig. 20-45 in Lodish et al.). That is, activation of insulin receptor leads to phosphorylation of IRS-1 which can activate an enzyme called phosphatidyl-inositol 3-hydroxyl kinase (PI-3 kinase). PI-3 kinase adds a phosphate group to the 3-0H group of the inositol moiety of a phosphatidyl inositol 4,5 bisphosphate (PIP2) in the membrane, converting it to phosphatidyl inositol 3,4,5 trisphosphate which can then bind to PKB. (Figure 20-45 depicts one too few phosphates on the inositol ring, but the text in the figure legend is correct). PKB in then phosphorylated, and activated, by membrane-associated kinases. PKB in turn induces a number of the short term effects of insulin, including activation of glucose uptake mechanisms, and activation of glycogen synthase, thus promoting uptake and storage of glucose when glucose is abundant in the bloodstream (e.g., following a meal).
Second, the metabolism of cells can be "fine-tuned" by different signaling molecules. Again the best-studied example involves insulin, which promotes uptake and storage of glucose by cells, especially muscle, fat cells (adipocytes) and liver cells (hepatocytes). Insulin is produced in the pancreas by cells that secrete it when levels of glucose in the bloodstream are high, and then acts through insulin receptors in target tissue to promote uptake and storage of glucose as glycogen. The body thus "socks away" glucose as glycogen when food is abundant (Fig. 20-46). At some time after a meal, glucose in the bloodstream is taken up and burned or stored by cells and the levels of glucose drops. This in turn causes cessation of insulin secretion but promotes secretion of a different hormone, glucagon, by the pancreas. Glucagon binds to receptors on target cells (essentially the same cell types that are sensitive to insulin) and promotes breakdown of glycogen and release of glucose back into the bloodstream. It does so by activating Protein Kinase A via G-protein coupled glucagon receptors, and so glucagon has essentially the same effects on cells as we've already discussed for epinephrine--except that epinephrine is only released by the adrenal gland during times of stress to ensure high blood levels of glucose. During normal activities, insulin and glucagon work together to ensure that the bloodstream contains a more or less constant concentration of glucose that can be taken up by cells to produce the ATP they need to function.
Third, different receptor proteins can interact with different G proteins in different cells, leading to very different outcomes. Table 20-5 lists some of the various kinds of G proteins that exist, and the various cellular responses that they can induce. In addition to the fact that cells contain different kinds of G proteins, that condition how they respond to the same kind of stimulus (such as epinephrine), it's recently been found that not only can the Ga subunit of G proteins serve to activate second messenger systems, but so can the Gb g subunits of the G protein. For example, white blood cells called phagocytes (such as macrophages) move to the site of an infection or injury because they can sense and move toward molecules that are released at those sites, a process called chemoattraction. Chemoattractants work by binding to G protein-coupled receptors on the surface of the phagocytes, inducing the dissociation of a G protein into Ga and Gb g subunits. The Gb g subunit then binds to a protein called phosphatidyl inosit0l -3-hydroxyl kinase (PI 3-kinase) that phosphorylates PIP2 in the membrane to make PIP3, which can bind to, and activate, a number of signal transduction molecules that in turn activate "downstream" effectors, and these in turn promote movement of the phagocyte "up" the concentration gradient of the chemoattractant molecules. The point here is that both the Ga and Gb g subunits can act within the same cell to cause somewhat different, complementary effects.
An example of interactions between different second messenger systems is the regulation of glycogen phosphorylase and glycogen synthase that I've already mentioned several times. In muscle cells, stimulation of beta-adrenergic receptors by epinephrine causes a rise in cAMP, and activation of Protein Kinase A which phosphorylates and activates glycogen phosphorylase kinase (GPK), in turn activating it. This enzyme activates glycogen phosphorylase leading, to breakdown of glycogen. At the same time PKA phosphorylates glycogen synthase, inhibiting it. In muscle, calcium released by muscle contraction binds to and also activates GPK (indeed, one of the subunits of GPK is the calcium-binding protein calmodulin). See Fig. 20-44a. Thus the combination of excitement (i.e., epinephrine in the bloodstream) and activity (muscle contraction) results in a synergistic activation of GPK and breakdown of glycogen to glucose for use in making ATP. In liver cells, beta-adrenergic receptors on the surface actually can bind to two second G protein systems that activate both protein kinase A and protein kinase C, through cAMP and DAG/Ca²⁺. PKC and PKA both phosphorylate in inhibit glycogen synthase. PKA and Ca²⁺ activate GPK to activate glycogen breakdown. (see Fig. 20-44.)
Finally, the activity of cell signaling systems can be modified in several ways including changes in the function of receptor proteins by phosphorylation or regulatory molecules and by reductions in the number of receptors caused by "ligand-dependent receptor mediated endocytosis" and degradation in lysosomes and endosomes.
As you might guess, alterations in cell signaling pathways are responsible for many human diseases, some of which I've already alluded to, and are thus clinically very important.. As I mentioned in an earlier lecture many drugs and toxins--such as cholera toxin, pertussis toxin, caffeine, etc.--alter the concentration of second messengers and thus alter cellular metabolism. One of the most widespread human diseases, and the main cause of blindness and still a major cause of death in the US is diabetes, which is a group of conditions that disrupt the regulation of blood glucose levels. Constitutively elevated levels of glucose in the bloodstream cause substantial long-term health problems, including kidney and eye damage. Some forms of diabetes are caused by destruction of the beta cells of the pancreas that produce insulin; it's thought but not known for sure, that destruction of the beta cells is an autoimmune reaction (they are destroyed by the body's own immune system) as a byproduct to a viral infection. This often happens to young people and cause "juvenile diabetes", which requires constant artificial supplies of insulin, by injection or now by implanted "pumps", throughout an individual's lifetime. Other forms of diabetes (adult-onset diabetes) are caused either by defects in the insulin receptor that impede its function (these conditions can be hereditary if the defect is a caused by a mutation in the receptor gene), or by reductions in the number of insulin receptors. Adults who are chronically overweight are often overweight because they eat too much and too often--this leads to a chronically high level of glucose in their blood streams, leading their pancreas to secrete high levels of insulin constantly. The high levels of insulin lead eventually to downregulation of the numbers of insulin receptors, so that cells become insensitive to insulin. In a vicious cycle the pancreas tries to produce more insulin, target cells produce fewer receptors and eventually become insulin resistant. This can be treated either with artificial insulin, or more effectively, with weight loss.