SUMMARY

• 13.1 Signal Transduction Depends on Molecular Circuits

  Most signal-transduction pathways are constructed with a similar set of components. A primary messenger, such as a hormone, binds to the extracellular part of a membrane-bound receptor. The messenger–receptor complex generates a second messenger inside the cell, which activates proteins that alter the biochemical environment inside the cell. Finally, means exist to terminate the signal-transduction pathway.

• 13.2 Receptor Proteins Transmit Information into the Cell

  Seven-transmembrane-helix receptors operate in conjunction with heterotrimeric G proteins. The binding of a hormone to a 7TM receptor triggers the exchange of GTP for GDP bound to the a subunit of the G protein. G_α proteins can transmit information in a number of ways. G_αs-GTP activates adenylate cyclase, an integral membrane protein that catalyzes the synthesis of cAMP. Cyclic AMP then activates protein kinase A by binding to its regulatory subunit, thus unleashing its catalytic chains. 7TM receptors activate G_αq proteins and the phosphoinositide pathway. The receptor-triggered activation of phospholipase C generates two intracellular messengers by hydrolysis of phosphatidylinositol 4,5-bisphosphate. Inositol trisphosphate opens calcium channels in the endoplasmic and sarcoplasmic reticulum membranes. Diacylglycerol activates protein kinase C.

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• 13.3 Some Receptors Dimerize in Response to Ligand Binding and Recruit Tyrosine Kinases

  Some ligands induce dimerization of the receptors to which they bind. Such a receptor contains an extracellular domain that binds the ligand, a transmembrane region, and a cytoplasmic domain that either binds a protein kinase or is a protein kinase. The growth-hormone receptor participates in an example of this type of signal-transduction pathway. Dimerization of the receptor activates Janus kinase 2, a protein kinase associated with the intracellular part of the receptor.

  Receptor tyrosine kinases, such as the epidermal-growth-factor receptor and the insulin receptor, have intracellular domains that are kinases. When such receptor tyrosine kinases dimerize and are activated, cross-phosphorylation takes place. The phosphorylated tyrosines in activated receptor tyrosine kinases serve as docking sites for signaling proteins and permit further propagation of the signal. A prominent component of such pathways is the small GTPase Ras. The Ras protein, like the G_a subunit, cycles between an inactive form bound to GDP and an active form bound to GTP.

• 13.4 Metabolism in Context: Insulin Signaling Regulates Metabolism

  The hormone insulin is secreted when blood concentration of glucose is high. Insulin binds to the insulin receptor, which is a receptor tyrosine kinase. The activated tyrosine kinase then phosphorylates insulin-receptor substrate. The signaling pathway continues, with the key result being an increase in glucose transporters in the cell membrane.

• 13.5 Calcium Ion Is a Ubiquitous Cytoplasmic Messenger

  Calcium ion acts by binding to calmodulin and other calcium sensors. Calmodulin contains four calcium-binding modules called EF hands that recur in other proteins. Ca²⁺–calmodulin activates target proteins by binding to them.

• 13.6 Defects in Signaling Pathways Can Lead to Diseases

  If the genes encoding components of the signal-transduction pathways are altered by mutation, pathological conditions, most notably cancer, may result. In their mutated form, these genes are called oncogenes. The normal counterparts are called proto-oncogenes and function in pathways that control cell growth and replication. Mutated versions of Ras are frequently found in human cancers.