rel="nofollow" href="#ulink_625da35f-e33a-53b7-8478-41fb3b59bcd3">3.3 summarizes the major signaling processes involving phospholipase C‐β. For medical research, G‐protein‐linked signaling pathways are of major interest, as they are used by many currently available pharmaceuticals. There are still many unknown steps in the process, which could prove interesting targets for new drugs to be developed.
Enzyme‐linked receptors can be activated by a signaling molecule (e.g. various growth factors that stimulate cell division) (Figures 3.8 and 3.11). In dimeric receptors, two units form an active receptor with enzyme domains on the cytosolic side. The dimerization process activates tyrosine kinases (Table 3.5) that begin to phosphorylate each other. They are termed receptor tyrosine kinase (RTK). The phosphotyrosine residues are recognized by specific adapter proteins that are activated by them and then cause the activation of other signaling proteins (Figure 3.11). Proteins of the Ras superfamily (monomeric GTPases) mediate signaling in most RTKs. Since such enzyme‐linked receptors are often found in tumor cells where they are overexpressed or permanently activated, their inhibition, especially the inhibition of tyrosine kinase, is a major strategy in the treatment of cancer. The drug Gleevec (STI‐571) binds to the ATP‐binding site and thus inhibits tyrosine kinases effectively.
Nitric oxide is a gaseous signaling mediator with many functions. It is being synthesized from arginine by NO synthases(NOS). In smooth muscles, e.g. those of the endothelium of blood vessels, NO induces a relaxation. NO activates guanylyl cyclase, leading to cGMP formation, which lead to the relaxation of smooth muscles.
Table 3.4 Some functions of trimeric G‐proteins.
| Family | Family members | Effective subunit | Some functions |
|---|---|---|---|
| I | Gs | α | Activates adenylyl cyclase and Ca2+ channels |
| Golf | α | Activates adenylyl cyclase in olfactory neurons | |
| II | Gi | α | Inhibits adenylyl cyclase |
| βγ | Activates K+ channels | ||
| Go | βγ | Activates K+ channels, inactivates Ca2+ channels | |
| Gt | α | Activates cGMP phosphodiesterase in photoreceptors | |
| III | Gq | α | Activates phospholipase C‐β |
| IV | G12/13 | α | Activates Rho GTPases to regulate the actin cytoskeleton |
Source: Alberts et al. (2015). Reproduced with permission of Garland Science.
Figure 3.10 Role of phospholipase C‐β in the production of second messengers IP3 and DAG.
Source: Alberts et al. (2015). Adapted with permission of Garland Science.
Figure 3.11 Signal transduction after activation of G‐protein and enzyme‐linked receptors. GPCR, G‐protein‐coupled receptor; GEF, guanine exchange factor.
Source: Alberts et al. (2015). Adapted with permission of Garland Science.
Table 3.5 Signal proteins that act via receptor tyrosine kinases.
| Signal protein | Receptor | Activity |
|---|---|---|
| Epidermal growth factor | EGF‐R | Stimulates cell growth and differentiation |
| Insulin | Insulin‐R | Enhances glucose consumption and protein synthesis |
| Insulin‐like growth factor | IGF‐1‐R | Stimulates cell growth and survival in many cell types |
| Nerve growth factor (NGF) | Trk R | Stimulates cell growth and survival of neurons |
| Platelet‐derived growth factor (PDGF) | PDGF‐R | Stimulates cell growth, differentiation and cell migration |
| Macrophage colony‐stimulating factor (MCSF) | MCSF‐R | Stimulates cell growth and differentiation of macrophages and monocytes |
| Fibroblast growth factors (FGF1–FGF24) | FGF‐R | Stimulates cell growth and differentiation |
| Vascular endothelial growth factor (VEGF) | VEGF‐R | Stimulates angiogenesis |
| Ephrin | Eph‐R | Stimulates angiogenesis and axon orientation |
R, receptor.
These signal pathways have in common that they amplify the original signal from a few signal molecules to thousands of second messengers (cAMP, Ca2+), which can trigger thousands of targets (
