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Secreted molecules. The most important secreted mol- ecules include growth factors, discussed later; cytokines, a term reserved for mediators of inflammation and immune responses (also discussed in Chapters 3 and 5); and hormones, which are secreted by endocrine organs and act on different cell types (Chapter 20). #202 | | |
Signaling pathways also can be classified into different types based on the spatial relationships between the sending and receiving cells: #203 | | |
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Paracrine signaling. Cells in just the immediate vicinity are affected. Paracrine signaling may involve trans- membrane “sending” molecules that activate receptors on adjacent cells or secreted factors that diffuse for only short distances. In some instances, the latter is achieved by having secreted factors bind tightly to ECM. #205 | | |
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Autocrine signaling occurs when molecules secreted by a cell affect that same cell. This can serve as a means to entrain groups of cells undergoing synchronous differ- entiation during development, or it can be used to amplify (positive feedback) or dampen (negative feed- back) a response. #207 | | |
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Synaptic signaling. Activated neurons secrete neurotrans- mitters at specialized cell junctions (synapses) onto target cells. #209 | | |
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Endocrine signaling. A hormone is released into the bloodstream and acts on target cells at a distance. #211 | | |
Regardless of the nature of an extracellular stimulus (paracrine, synaptic, or endocrine), the signal it conveys is transmitted to the cell via a specific receptor protein. Signaling molecules (ligands) bind their respective recep- tors and initiate a cascade of intracellular events culminat- ing in the desired cellular response. Ligands usually have high affinities for receptors and at physiologic concentra- tions bind receptors with exquisite specificity. Receptors may be present on the cell surface or located within the cell (Fig. 1.12): #212 | | |
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Intracellular receptors include transcription factors that are activated by lipid-soluble ligands that easily transit plasma membranes. Examples include vitamin D and steroid hormones, which activate nuclear hormone receptors. In other settings, a small and/or nonpolar signaling ligand can diffuse into adjacent cells. Such is the case for nitric oxide (NO), through which endothe- lial cells regulate intravascular pressure. NO is gener- ated by an activated endothelial cell and then diffuses into adjacent vascular smooth muscle cells; there it activates guanylyl cyclase to generate cyclic GMP, an intracellular second signal that causes smooth muscle relaxation. #214 | | |
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Cell-surface receptors are generally transmembrane pro- teins with extracellular domains that bind activating ligands. Depending on the receptor, ligand binding may #216 | | |
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open ion channels (typically at the synapse between #218 | | |
electrically excitable cells), (2) activate an associated GTP-binding regulatory protein (G protein), (3) activate an endogenous or associated enzyme, often a tyrosine kinase, or (4) trigger a proteolytic event or a change in protein binding or stability that activates a latent tran- scription factor. Activities (2) and (3) are associated with growth factor signaling pathways that drive cell prolif- eration, whereas activity (4) is a common feature of mul- tiple pathways (e.g., Notch, Wnt, and Hedgehog) that regulate normal development. Understandably, signals transduced by cell surface receptors are often deranged in developmental disorders and in cancers. #219 | | |
Signal Transduction Pathways #220 | | |
Binding of a ligand to a cell surface receptor mediates sig- naling by inducing clustering of the receptor (receptor crosslinking) or other conformational changes (Fig. 1.12). #221 | | |
The common theme is that all of these perturbations cause a change in the physical state of the intracellular domain of the receptor, which then triggers additional biochemical events that lead to signal transduction. #222 | | |
Cellular receptors are grouped into several types based on the signaling mechanisms they use and the intracel- lular biochemical pathways they activate (Fig. 1.12). Receptor signaling most commonly leads to the formation or modification of biochemical intermediates and/or acti- vation of enzymes, and ultimately to the generation of active transcription factors that enter the nucleus and alter gene expression: #223 | | |
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Receptors associated with kinase activity. Downstream phosphorylation is a common pathway of signal trans- duction. Changes in receptor geometry can stimulate intrinsic receptor protein kinase activity or promote the enzymatic activity of recruited intracellular kinases. These kinases add charged phosphate residues to target molecules. Tyrosine kinases phosphorylate spe- cific tyrosine residues, whereas serine/threonine kinases add phosphates to distinct serine or threonine residues, and lipid kinases phosphorylate lipid substrates. For every phosphorylation event, there is also a potential counter-regulatory phosphatase, an enzyme that can remove the phosphate residue and thus modulate sig- naling; usually, phosphatases play an inhibitory role in signal transduction. #225 | | |
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Receptor tyrosine kinases (RTKs) are integral membrane proteins (e.g., receptors for insulin, epidermal growth factor, and platelet-derived growth factor [PDGF]); ligand-induced crosslinking activates intrinsic tyrosine kinase domains located in their cytoplasmic tails. #227 | | |
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Several kinds of receptors have no intrinsic catalytic activity (e.g., immune receptors, some cytokine recep- tors, and integrins). For these, a separate intracellular protein—known as a nonreceptor tyrosine kinase— interacts with receptors after ligand binding and phos- phorylates specific motifs on the receptor or other proteins. The cellular homolog of the transforming protein of the Rous sarcoma virus, called SRC, is the prototype for an important family of such nonreceptor tyrosine kinases (Src-family kinases). SRC contains unique functional regions called Src-homology (SH) domains; SH2 domains typically bind to receptors phosphorylated by another kinase, allowing the aggre- gation of multiple enzymes, whereas SH3 domains mediate protein–protein interactions, often involving proline-rich domains. #229 | | |
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G-protein coupled receptors are polypeptides that charac- teristically traverse the plasma membrane seven times (hence their designation as seven-transmembrane or serpentine receptors); more than 1500 such receptors have been identified. After ligand binding, the receptor associates with an intracellular guanosine triphosphate (GTP)-binding protein (G protein). At baseline, these G proteins contain guanosine diphosphate (GDP); interac- tion with a receptor-ligand complex results in G protein activation through the exchange of GDP for GTP. Down- stream signaling typically involves the generation of cAMP, and inositol-1,4,5,-triphosphate (IP3), the latter releasing calcium from the ER. #231 | | |
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Nuclear receptors. Lipid-soluble ligands can diffuse into cells where they interact with intracellular proteins to form a receptor-ligand complex that directly binds to nuclear DNA; the results can be either activation or repression of gene transcription. #233 | | |
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Other classes of receptors. Other receptors—originally rec- ognized as important for embryonic development and cell fate determination—have since been shown to par- ticipate in the functions of mature cells, particularly within the immune system. These pathways rely on protein:protein interactions, rather than enzymatic activities, to transduce signals, which may serve to allow for very precise control. #235 | | |
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Receptor proteins of the Notch family: ligand binding to Notch receptors leads to proteolytic cleavage of the receptor and subsequent nuclear translocation of the cytoplasmic domain (intracellular Notch) to form a transcription complex. #237 | | |
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Wnt protein ligands act through a pathway involving transmembrane Frizzled family receptors, which reg- ulate the intracellular levels of β-catenin. In the absence of Wnt, β-catenin is targeted for ubiquitin- directed proteasome degradation. Wnt binding to Frizzled (and other coreceptors) recruits other pro- teins that disrupt the degradation-targeting complex. This stabilizes β-catenin, allowing it to translocate to the nucleus and form a transcription complex. #239 | | |
Modular Signaling Proteins, Hubs, and Nodes #240 | | |
The traditional linear view of signaling—that receptor activation triggers an orderly sequence of biochemical inter- mediates that ultimately leads to changes in gene expression and the desired biological response—is oversimplified. Instead, it is increasingly clear that any initial signal results in multiple primary and secondary effects, each of which contributes in varying degrees to the final outcome. This is particularly true of signaling pathways that rely on enzymatic activities, which typically modulate a web of polypeptides with complex interactions. For example, phosphorylation of any given protein can allow it to associ- ate with a host of other molecules, resulting in multiple effects such as: #241 | | |
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Enzyme activation (or inactivation) #243 | | |
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Nuclear (or cytoplasmic) localization of transcription factors (see later) #245 | | |
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Transcription factor activation (or inactivation) #247 | | |
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Actin polymerization (or depolymerization) #249 | | |
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