17.7: 17.7 signal switching (2023)

A. G protein-mediated signaling by PKA (protein kinase A)

GTP-binding proteins(G-Proteine) converts extracellular signals and thus induces its productionsecond messengermolecules in cells. When hormones or other effector molecules (signaling molecules) bind to their membrane receptors, an allosteric change occurscytoplasmicThe receptor domain increases the affinity of the cytoplasmic domain of the receptor for G proteins on the inner surface of the plasma membrane. G proteins aremutatedcomposed of \(\alpha \), \(\beta \), and \(\gamma \) subunits embedded in the cytoplasmic surface of responsive cell membranes. G protein-mediated signaling is illustrated in the seven steps on the next page.

The receptor changes shape when it binds its effector signaling molecule (steps 1, 2). In this conformation, the receptor recognizes and binds to the G protein trimer on the cytoplasmic side of the plasma membrane (step 3). Upon binding of the trimer to the receptor, GTP displaces GDP\(\alpha \) subunitof protein G (step 4).

After a conformational change, the\(\alpha \) subunitdiffers from the subunits \(\beta \) and \(\gamma \) (step 5). In this figure, the GTP \(\alpha \) subunit can now bind to a transmembrane enzyme,Adenylcyclase(Step 6). Finally, the first is the extracellular chemical signalwould translateto an intracellular reaction involving second messenger molecules (step 7). In this case, the other is the messengerLager. The knownfight or give upThe response to adrenaline in higher animal hepatocytes is a good example of a cAMP-mediated cellular response. After adrenaline binds to its receptors, G proteins rebind to the cytoplasmic side of the receptor, which then binds to adenylate cyclase. cAMP binds and activatesProteinkinase A(PKA), getting startedreinforcement cascadeAnswer. Some details of a G protein-mediated signal amplification cascade are shown in the figure on the next page.

After activation of adenylate cyclase (steps 1 and 2 in the scheme), cAMP is synthesized and binds to two of the four subunits in ainactive PKA(Step 3). A conformational change cleaves the tetramer into two inactive cAMP-bound subunits and twoactive PKAsubunits (step 4). Everyactive PKAEnzyme catalyzes the phosphorylation and activation of an enzyme calledPhosphorylase-Kinase(Trin 5).

In step 6, the phosphorylase catalyzes the kinaseGlykogenphosphorylasephosphorylation. Finally, at the endphosphorylation cascade, the most activeGlykogenphosphorylasecatalyzes glycogen hydrolysis to glucose-1-phosphate (step 7). This leads to a rapid export of free glucose from the liver cells into the circulatory system. Recall how this works by considering the conversion of glucose-1-phosphate (G-1-P) to G-6-P in glycolysis and its fate in gluconeogenesis. Of course, increasing circulating glucose provides the energyfight or give upDecision.

317 G protein activation of protein kinase A and αfight or give upAnswer

In addition to activating glycogen-degrading enzymes, cAMP-activated PKA mediates cellular responses to various effectors, resulting in a phosphorylation cascade

• Activation of enzymes that catalyze glycogen synthesis.
• Activate itLipasehydrolyze fatty acids from triglycerides.
• Assembly of microtubules.
• Dissection of microtubules.
• Mitogenic effects (activation of replication enzymes).
• Activation of transcription factors that increase/decrease gene expression.

When the cellular response is no longer needed by the body, it must naturally stop producing the signaling molecules (hormones or other effectors). When their levels drop, the effector molecules dissociate from their receptors and the response stops. All of this is possible because the binding of signals to their receptors is freely reversible! This is animated for G-protein based signaling in the link below.

316 G protein signaling

B. Signal transduction by PKC

Many reactions involving G proteins are triggered by activation of the integral membraneAdenylcyclase. Another G protein-mediated signaling pathway generates other second messengers.Proteinkinase C(PKC) plays an important role in the activation of these other second messengers and subsequentlyphosphorylation cascadesThe activation of only a few enzyme molecules in the cell leads to the activation of many other enzymes. HowPKA,PKC- also mediated signal transductionamplifierthe cell's first molecular response to the effector. The role of G proteins is for PKA and similarPKC signaling. Responses can have different effects in different cells... or even in the same cells by using different effector signals. However, PKC and PKA signaling differ in that PKC activation requires an additional step and the formation of two intracellular messenger molecules. The events leading up to its activationPKCis shown below.

Here are the details of the steps that lead to itPKCActivation. An effector signaling molecule binds to its receptor and activates an integrated membranePhospholipase CEnzyme.Phospholipase Ccatalyzes the formation of cytosolsInositoltrifosfat(IP₃) and membrane boundDiacylglycerin(Tag), two of these other intracellular second messenger molecules. IP3 interacts with receptors in the smooth endoplasmic reticulum and causes the release of bound Ca++ ions into the cytoplasm. Finally,Ca²⁺Ions and DAG are activatedProteinkinase C(PKC), which then triggers a cascade of enhanced phosphorylation leading to cell-specific responses.

318 G protein activation of protein kinase C and phospholipase C

Effects mediated by protein kinase C include:

• release of neurotransmitters.
• Hormone secretion (growth hormone, leukinogenic hormone, testosterone) leading to cell growth, cell division and differentiation.
• Glycogen hydrolysis, Fat synthesis.

In addition, independentPhospholipase CImpacts include:

• Breakdown of glycogen in the liver.
• Starch secretion of the pancreas.
• aggregation of blood platelets.

PKA and PKC areSerin-Threonin-Kinasethat they place phosphates on serine or threonine in the target polypeptides. Next, let's look at tyrosine kinases.

C. Receptor tyrosine kinase signaling

The intracellular activity of these receptors resides in the cytoplasmic domain of the receptor itself. Once bound to its effector, the receptor kinase catalyzes the phosphorylation of specific tyrosine amino acids on target proteins. By studying his deednerve growth factor(NGF) Andepidermal growth factor(EGF) by stimulating the growth and differentiation of nerves and skin, was discovered by Stanley Cohen and Rita Levi-MontalciniEGF receptor, the firstenzyme bound Tyrosinkinase... and won the Nobel Prize in Physiology or Medicine in 1986! View the animation of receptor kinase signaling in the link below (see the following sections for a description).

319 receptor kinase signal transduction

Monomeric membrane receptor kinases dimerize upon binding active ligand and then contain a sulfhydryl groupSch₂Proteinbinds to any monomer. This activates the kinase domain of the receptor. After multiple cross-phosphorylations of receptor monomers, SH₂The proteins are removed, allowing the receptors to interact with other cytoplasmic proteins to continue the reaction pathway. The characteristic response to EGF and NGF signaling is cell proliferation. Not surprisingly, mutations associated with cancer cells are commonly found in signaling pathways that lead to cell proliferation (growth and division). Genes that cause cancer orOncogenes, was actually first discovered in viruses, but J. Michael Bishop and Harold Varmus received the 1964 Nobel Prize in Physiology or Medicine for showing that cells were in fact the origin of a chicken retrovirus (Rous sarcoma virus).Oncogenic agentturn out to be mutations of genes for proteins in mitogenic signal transduction pathways. Under normal conditions, mitogenic chemical signals (such asEGF) bind to their receptors and cause the target cells to divide.

TheRasProtein-induced activation of a phosphorylation cascade leading toMAP(mitogen-activated protein;)Kinaseis an example of such a signal transduction pathway, which plays a central role in many receptor kinase signaling pathways. The Ras gene was one of the first discovered oncogenes, the mutation of which leads to uncontrolled cell division, i.e. cancer. Ras gene/protein activity could actually be responsible for up to 30% of all cancers!

320 The RAS oncogene, its normal mitogenic effects and cancer

MAP-Kinase-PhosphorylatorThe transcription factorand other core proteins that affect gene activity and lead to cell proliferation and differentiation, as shown below.

D. Signal transduction and development

We have seen that signaling typically requires some signaling molecules that interact with some cell surface receptors to amplify a response in a cascade of enzymatic reactions, usually phosphorylations, and activate (or inactivate) target proteins. Amplification cascades can take advantage of a single effector-receptor interaction and amplify its effect on the cell by orders of magnitude, making signaling systems fast and highly efficient. The spectrum of cellular and systemic (organism) responses to the same chemical signal is broad and complex. Different cell types may have receptors for the same effector but respond differently. Adrenaline, for example, targets cells in the liver and blood vessels, among others, and has different effects on each. Adrenaline is also a neurotransmitter. Apparently, as organisms evolved, they became more complex in response to environmental cues, adapting by incorporating pre-existing signaling systems to service new signaling pathways. Just as the same signal transduction event can give rise to different response pathways in different cells, evolution has allowed for the involvement of different signal transduction pathwayscrossword. This happens when two different signal transduction pathways cross in the same cells. In one example, cAMP generated at the front end of the PKA signaling pathway can activate (or under appropriate conditions inhibit) enzymes in the MAP kinase pathway. These effects lead to changes in the levels of active or inactive transcription factors and can therefore regulate the expression of a gene using two (or more) signals. We're just beginning to understand what's less linear.