Binding of a ligand to a cell surface receptor mediates signaling by inducing clustering of the receptor (receptor crosslinking) or other types of physcial perturbations (Fig. 1). 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.

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.

Cellular receptors are grouped into several types based on the signaling mechanisms they use and the intracellular biochemical pathways they activate (Fig. 1). Receptor signaling typically leads to the formation or modification of biochemical intermediates and/or activation of enzymes, and ultimately to the generation of active transcription factors that enter the nucleus and alter gene expression:

• Receptors associated with kinase activity. Downstream phosphorylation is a common pathway (but not the only one) by which these signals are transduced. Thus, alterations in receptor geometry can elicit intrinsic receptor protein kinase activity or promote the enzymatic activity of recruited intracellular kinases—resulting in the addition of charged phosphate residues to target molecules. Tyrosine kinases phosphorylate specific 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 phosphatase, an enzyme that can remove the phosphate residue and thus modulate signaling; usually, phosphatases play an inhibitory role in signal transduction.

• Receptor tyrosine kinases (RTKs) are integral membrane proteins (e.g., receptors for insulin, epidermal growth factor, and platelet derived growth factor); ligand-induced cross-linking activates intrinsic tyrosine kinase domains located in their cytoplasmic tails.

• Several kinds of receptors have no intrinsic catalytic activity (e.g., immune receptors, some cytokine receptors, and integrins). For these, a separate intracellular protein—known as a nonreceptor tyrosine kinase—phosphorylates 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, such as Src-homology 2 (SH2) and Src-homology 3 (SH3) domains. SH2 domains typically bind to receptors phosphorylated by another kinase, allowing the aggregation of multiple enzymes. SH3 domains mediate other protein-protein interactions, often involving proline-rich domains.

• G-protein coupled receptors are polypeptides that characteristically 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) that contains guanosine diphosphate (GDP). G-protein interaction with a receptor-ligand complex results in activation through the exchange of GDP for GTP. Downstream receptor mediated signaling events result in the generation of cyclic AMP (cAMP), and inositol-1,4,5,-triphosphate (IP3), the latter releasing calcium from the endoplasmic reticulum.

• 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.

• Other classes of receptors. Other receptors—originally recognized as important for embryonic development and cell fate determination—have since been shown to participate in the functions of mature cells, particularly within the immune system.

• Receptor proteins of the Notch family fall in this category; ligand binding to Notch receptors leads to proteolytic cleavage of the receptor and subsequent nuclear translocation of the cytoplasmic piece (intracellular Notch) to form a transcription complex.

• Wnt protein ligands can also influence cell development through a pathway involving transmembrane Frizzled family receptors, which regulate the intracellular levels of β-catenin. Normally, β-catenin is constantly targeted for ubiquitin-directed proteasome degradation. However, Wnt binding to Frizzled (and other co-receptors) recruits yet another intracellular protein (Disheveled) that leads to disruption of the degradation-targeting complex. The stabilized pool of β-catenin molecules then translocates to the nucleus, where β-catenin forms a transcriptional complex.

Modular Signaling Proteins, Hubs, and Nodes. The traditional linear view of signaling—that receptor activation triggers an orderly sequence of biochemical intermediates that ultimately leads to changes in gene expression and the desired biological response—is almost certainly oversimplified. Instead, it is increasingly clear that any initial signal results in multiple diverging effects, each of which contributes in varying degrees to the final outcome. For example, specific phosphorylation of any given protein can allow it to associate with a host of other molecules, resulting in multiple effects such as:

• Enzyme activation (or inactivation)

• Nuclear (or cytoplasmic) localization of transcription factors (see later)

• Transcription factor activation (or inactivation)

• Actin polymerization (or depolymerization)

• Protein degradation (or stabilization)

• Activation of feedback inhibitory (or stimulatory) loops

Adaptor proteins play a key role in organizing intracellular signaling pathways. These proteins function as molecular connectors that physically link different enzymes and promote the assembly of complexes; adaptors can be integral membrane proteins or cytosolic proteins. A typical adaptor may contain a few specific domains (e.g., SH2 or SH3) that mediate protein-protein interactions. By influencing which proteins are recruited to signaling complexes, adaptors can determine downstream signaling events.

By analogy with computer networks, the protein-protein complexes can be considered nodes and the biochemical events feeding into or emanating from these nodes can be thought of as hubs. Signal transduction can therefore be visualized as a kind of networking phenomenon; understanding this higher order complexity is the province of systems biology, involving a “marriage” of biology and computation.

Transcription Factors. Most signal transduction pathways ultimately influence cellular function by modulating gene transcription through the activation and nuclear localization of transcription factors. Conformational changes of transcription factors (e.g., following phosphorylation) can allow their translocation into the nucleus or can expose specific DNA or protein binding motifs. Transcription factors may drive the expression of a relatively limited set of genes or may have much more widespread effects on gene expression. Among the transcription factors that regulate the expression of genes that are needed for growth are MYC and JUN, while a transcription factor that triggers the expression of genes that lead to growth arrest is p53. Transcription factors have a modular design, often containing domains that bind DNA and that interact with other proteins, such as components of the RNA polymerase complex, that are needed to drive transcription.

• The DNA-binding domain permits specific binding to short DNA sequences. While most interest historically has been focused on binding of transcription factors to gene promoters, it is now appreciated that most transcription factors bind widely throughout genomes, with the majority of binding occurring in long-range regulatory elements such as enhancers. Enhancers are usually located in the “neighborhood” close to genes, but are sometimes far away; it is even suspected that some may be located on other chromosomes! These insights highlight the importance of chromatin organization in regulating gene expression, both normal and pathologic.

• For a transcription factor to induce transcription, it must also possess protein: protein interaction domains that directly or indirectly recruit histone modifying enzymes, chromatin remodeling complexes, and (most importantly) RNA polymerase—the large multiprotein enzymatic complex that is responsible for RNA synthesis.

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