Many growth factor receptors activate protein kinase cascades within the cell.

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Many growth factor receptors activate protein kinase cascades within the cell.

Many growth factor receptors activate protein kinase cascades within the cell.
Many growth factor receptors activate protein kinase cascades within the cell.

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Three common pathways are shown. After binding of ligand, the receptor dimerizes and becomes phosphorylated. A cascade of kinase activations is initiated resulting in a change in target gene transcription. GTP, Guanosine triphosphate; JAK, janus kinase; MAP, mitogen-activated kinase; PI3K, phosphoinositide 3-kinase; RAS, rat sarcoma protein; STAT, signal transducer and activator of transcription.

PI3K-protein kinase B pathway, the RAS-MAP kinase pathway, and the JAK-STAT pathway (Fig. 3.36).

A large number of signaling ligands bind to G-protein–coupled receptors (GPCRs). Most hormones and many drugs have their effects through G-protein–linked cascades. G-protein–coupled receptors act indirectly through a membrane-bound trimeric G-protein that binds GTP when activated by the receptor. The activated α subunit of the trimeric G-protein influences the activity of specific target enzymes. The target enzymes of G-proteins produce second messengers that trigger specific intracellular cascades and alter cell function (Fig. 3.37). The α subunit of G-proteins has intrinsic enzyme activity that degrades GTP into GDP and Pi after a time. When GTP is bound, the G-protein is in the right conformation to activate its downstream targets, but when GTP is hydrolyzed to GDP and Pi, the G-protein resumes its inactive conformation and the activity of the signaling cascade is terminated.

There are three principal G-protein–coupled signaling systems that, when activated, alter the intracellular concentration of one or more second messengers (see Fig. 3.37). Numerous receptors activate trimeric G-proteins whose α subunit stimulates adenylyl cyclase to produce the second messenger cyclic adenosine monophosphate (cAMP). These G-proteins are called Gs. An increase in cAMP concentration is linked to different signaling cascades in different cell types. For example, cAMP causes glycogen breakdown in liver cells, increased force of contraction in cardiac cells, and increased secretion by glandular cells. Various cell types respond differently to the same second messenger because of differences in enzymes and other proteins in the cell.

Another important G-protein–coupled cascade is mediated by G-proteins called Gq whose α subunit stimulates the enzyme phospho- lipase C. Phospholipase C cleaves a membrane phospholipid (PI[4,5] P2) to form two second messengers: inositol 1,4,5-trisphosphate (IP3)

and diacylglycerol (DAG) (see Fig. 3.37). The IP3 travels to the ER, where it stimulates the release of Ca2+ into the cytoplasm. The Ca2+ then triggers a change in cell function. DAG remains bound to the inner surface of the plasma membrane and can trigger several different intracellular cascades. Two important targets are the protein kinase C pathway and the eicosanoid pathway. Protein kinase C is a key enzyme in the growth response. The eicosanoid pathway results in the production of several arachidonic acid derivatives, including prostaglandins. These products are often secreted by the cell as signaling molecules to other nearby cells. Prostaglandins are important mediators of inflammation and platelet function.

The third trimeric G-protein type is called Gi because it is inhibitory to the production of cAMP. GPCRs such as the acetylcholine receptor in the heart activate Gi, whose α subunit then inhibits adenylyl cyclase (see Fig. 3.37). In this case the γβ subunit of Gi is also activated and opens membrane potassium channels in the heart, which tend to slow the heart rate. Although Gs, Gq, and Gi are the primary trimeric G-protein signaling cascades, others have been described (Table 3.1).

In addition to the four second messengers already mentioned (cAMP, IP3, DAG, and Ca

2+) there is a fifth called cyclic guanosine monophosphate (cGMP), which is produced by the enzyme guanylyl cyclase (Fig. 3.38). The primary activator of guanylyl cyclase is a small lipid-soluble gas molecule called nitric oxide. Nitric oxide is an important signaling molecule with widespread targets. It functions as a neurotransmitter in the brain and is an important smooth muscle relaxant in the vascular system. cGMP is also produced by a special class of enzyme-linked receptors (see Fig. 3.38).

To be effective at communicating signals, all the receptor systems must be quickly turned off so that they can be responsive to the next incoming signal. A variety of strategies are used to quench the signaling