In humans and other multicellular organisms, specific signal molecules are released from cells in one organ and are sensed by cells in other organs throughout the body. The message initiated by an extracellular ligand is converted into specific changes in metabolism or gene expression by means of often complex networks referred to as signal-transduction pathways. These pathways amplify the initial signal and lead to changes in the properties of specific effector molecules.

14.1 Heterotrimeric G Proteins Transmit Signals and Reset Themselves

Epinephrine binds to a cell-surface protein called the β-adrenergic receptor. This receptor is a member of the seven-transmembrane-helix receptor family, so named because each receptor has seven α helices that span the cell membrane. When epinephrine binds to the β -adrenergic receptor on the outside of the cell, the receptor undergoes a conformational change that is sensed inside the cell by a signaling protein termed a heterotrimeric G protein. The α subunit of the G protein exchanges a bound GDP molecule for GTP and concomitantly releases the heterodimer consisting of the β and γ subunits. The α subunit in the GTP form then binds to adenylate cyclase and activates it, leading to an increase in the concentration of the second messenger cyclic AMP. This increase in cyclic AMP concentration, in turn, activates protein kinase A. Other 7TM receptors also signal through heterotrimeric G proteins, although these pathways often include enzymes other than adenylate cyclase. One prominent pathway, the phosphoinositide pathway, leads to the activation of phospholipase C, which cleaves a membrane lipid to produce two secondary messengers, diacylglycerol and inositol 1,4,5-trisphosphate. An increased IP₃ concentration leads to the release of calcium ion, another important second messenger, into the cell. G-protein signaling is terminated by the hydrolysis of the bound GTP to GDP.

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14.2 Insulin Signaling: Phosphorylation Cascades Are Central to Many Signal-Transduction Processes

Protein kinases are key components in many signal-transduction pathways, including some for which the protein kinase is an integral component of the initial receptor. An example of such a receptor is the membrane tyrosine kinase bound by insulin. Insulin binding causes one subunit within the dimeric receptor to phosphorylate specific tyrosine residues in the other subunit. The resulting conformational changes dramatically increase the kinase activity of the receptor. The activated receptor kinase initiates a signaling cascade that includes both lipid kinases and protein kinases. This cascade eventually leads to the mobilization of glucose transporters to the cell surface, increasing glucose uptake. Insulin signaling is terminated through the action of phosphatases.

14.3 EGF Signaling: Signal-Transduction Systems Are Poised to Respond

Only minor modifications are necessary to transform many signal-transduction proteins from their inactive into their active forms. Epidermal growth factor also signals through a receptor tyrosine kinase. EGF binding induces a conformational change that allows receptor dimerization and cross-phosphorylation. The phosphorylated receptor binds adaptor proteins that mediate the activation of Ras, a small G protein. Activated Ras initiates a protein kinase cascade that eventually leads to the phosphorylation of transcription factors and changes in gene expression. EGF signaling is terminated by the action of phosphatases and the hydrolysis of GTP by Ras.

14.4 Many Elements Recur with Variation in Different Signal-Transduction Pathways

Protein kinases are components of many signal-transduction pathways, both as components of receptors and in other roles. Second messengers, including cyclic nucleotides, calcium, and lipid derivatives, are common in many signaling pathways. The changes in the concentrations of second messengers are often much larger than the changes associated with the initial signal owing to amplification along the pathway. Small domains that recognize phosphotyrosine residues or specific lipids are present in many signaling proteins and are essential to determining the specificity of interactions.

14.5 Defects in Signal-Transduction Pathways Can Lead to Cancer and Other Diseases

Genes encoding components of signal-transduction pathways that control cell growth are often mutated in cancer. Some genes can be mutated to forms called oncogenes that are active regardless of appropriate signals. Monoclonal antibodies directed against cell-surface receptors that participate in signaling have been developed for use in cancer treatment. Our understanding of the molecular basis of cancer is leading to the development of anticancer drugs directed against specific targets, such as the specific kinase inhibitor Gleevec.