An individual cell is chronically exposed to a remarkable variety of signals, which it must sort through and integrate into some sort of rational output. Some signals may induce a given cell type to differentiate, others may stimulate proliferation, and yet others may direct the cell to perform a specialized function. Multiple signals received in combination may trigger yet another totally unique response. Many cells require certain inputs just to continue living; in the absence of appropriate exogenous signals, they die by apoptosis.

The signals that most cells respond to can be classified into several groups:

• Damage to neighboring cells and pathogens. Many cells have an innate capacity to sense and respond to damaged cells (danger signals), as well as foreign invaders such as microbes. The receptors that detect these dangers are discussed in Chapters 3 and 6.

• Contact with neighboring cells, mediated through adhesion molecules and/or gap junctions. As mentioned previously, gap junction signaling is accomplished between adjacent cells via hydrophilic connexons that permit the movement of small ions (e.g., calcium), various metabolites, and potential second messenger molecules like cAMP, but not larger macromolecules.

• Contact with ECM, mediated through integrins, which are discussed in the context of leukocyte attachment to other cells during inflammation in Chapter 3.

• Secreted molecules. The most important secreted molecules include growth factors, discussed later; cytokines, a term reserved for mediators of inflammation and immune responses (also discussed in Chapters 3 and 6); and hormones, which are secreted by endocrine organs and act on different cell types (Chapter 24).

Extracellular cell-cell signaling pathways are classified into different types, based on the distance over which the signal functions:

• Paracrine signaling. Cells in just the immediate vicinity are affected. To accomplish this, there can be only minimal diffusion, with the signal being rapidly degraded, taken up by other cells, or trapped in the ECM.

• Autocrine signaling occurs when molecules secreted by a cell affect that same cell. This can be a means to entrain groups of cells undergoing synchronous differentiation during development, or can be used to amplify a response or for its feedback inhibition.

• Synaptic signaling. Activated neurons secrete neurotransmitters at specialized cell junctions (synapses) onto target cells.

• Endocrine signaling. A mediator is released into the bloodstream and acts on target cells at a distance.

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 receptors and initiate a cascade of intracellular events culminating in the desired cellular response. Ligands usually have high affinities for receptors and at physiologic concentrations bind receptors with exquisite specificity. Receptors may be present on the cell surface or located within the cell (Fig. 1):

• Intracellular receptors are transcription factors that are activated by lipid-soluble ligands that can easily cross the plasma membrane. Examples of cell-permeable, hydrophobic ligands for this class of receptor include vitamin D and steroid hormones, which activate nuclear hormone receptors. Uncommonly, the signaling ligand diffuses into adjacent cells; this is the case with nitric oxide, which directly activates the enzyme guanylyl cyclase to generate cyclic GMP, an intracellular second signal.

• Cell-surface receptors are generally transmembrane proteins with extracellular domains that bind soluble secreted ligands. Depending on the receptor, ligand binding can then (1) open ion channels (typically at the synapse between 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 transcription factor. Activities (2) and (3) are associated with growth factor signaling pathways that drive cell proliferation, while activity (4) is a common feature of multiple 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.

Fig1. Receptor-mediated signaling. A, Categories of signaling receptors, including receptors that utilize a nonreceptor tyrosine kinase; a receptor tyrosine kinase; a nuclear receptor that binds its ligand and can then influence transcription; a seven-transmembrane receptor linked to heterotrimeric G proteins; Notch, which recognizes a ligand on a distinct cell and is cleaved yielding an intracellular fragment that can enter the nucleus and influence transcription of specific target genes; and the Wnt/Frizzled pathway where activation releases intracellular β-catenin from a protein complex that normally drives its constitutive degradation. The released β-catenin can then migrate to the nucleus and act as a transcription factor. Lrp5/Lrp6, low-density-lipoprotein (LDL) receptor related proteins 5 and 6, are highly homologous and act as co-receptors in Wnt/Frizzled signaling. B, Signaling from a tyrosine kinase-based receptor. Binding of the growth factor (ligand) causes receptor dimerization and autophosphorylation of tyrosine residues. Attachment of adapter (or bridging) proteins couples the receptor to inactive, GDP-bound RAS, allowing the GDP to be displaced in favor of GTP and yielding activated RAS. Activated RAS interacts with and activates RAF (also known as MAP kinase kinase kinase). This kinase then phosphorylates MAPK (mitogen-activated protein kinase) and activated MAP kinase phosphorylates other cytoplasmic proteins and nuclear transcription factors, generating cellular responses. The phosphorylated tyrosine kinase receptor can also bind other components, such as phosphatidyl 3-kinase (PI3 kinase), which activates other signaling systems. The cascade is turned off when the activated RAS eventually hydrolyzes GTP to GDP converting RAS to its inactive form. Mutations in RAS that lead to delayed GTP hydrolysis can thus lead to augmented proliferative signaling. GDP, Guanosine diphosphate; GTP, guanosine triphosphate; mTOR, mammalian target of rapamycin.

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مواضيع ذات صلة

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Proliferation and the Cell Cycle

Growth Factors and Receptors

Signal Transduction Pathways

Cellular Metabolism and Mitochondrial Function

Waste Disposal: Lysosomes and Proteasomes

Biosynthetic Machinery: Endoplasmic Reticulum and Golgi

Cytoskeleton and Cell-Cell Interactions

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Cytoplasmic Structures in Prokaryotic Cell

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Cell Differentiation