Signal Transduction

Introduction to Signal Transduction

The term signal transduction refers to the movement of a signal from the outside of a cell to the inside, where the incoming signal can lead to changes in cellular activity such as gene transcription. This occurs in all organisms, from the very simple bacteria responding to changes in their environment, to complex organisms that use cell signaling to control and regulate their development and organization in tissues.

Cell signaling can be grouped into 3 classes by means of how the incoming signal is transduced across the plasma membrane. The first group is comprised of the steroid hormones and their receptors. The cholesterol-derived steroid hormones are able to diffuse through the cell membrane and find their target receptor. Protein hormones and growth factors bind to their receptors at the cell surface and are internalized by receptor-mediated endocytosis. The receptors of the third group (also located at the cell membrane), undergo a conformational change upon binding their respective ligands. This conformational shift alters the receptorÕs physical properties, leading to changes in the target cell.

The steroid hormone receptors are a family of highly related proteins that are normally located in the cytoplasm, although some are present in the cell nucleus. On binding to its specific ligand, the steroid hormone receptor undergoes a conformational shift and are released from protein chaperones (such as HSP90). If the receptor resides in the cytoplasm, this also uncovers a nuclear localization signal sequence which facilitates its movement to the nucleus. Once in the nucleus, these hormones bind to specific DNA transcription elements which lead to alterations in gene expression (reviewed in Beato and Klug, 2000).

Other cell signals are either not hydrophobic enough or are too big to diffuse through the plasma membrane, or both. This is the situation with many protein hormones and growth receptors. In these cases, the signal is transduced across the membrane by a process in which the entire receptor/ligand complex is endocytosed into the interior of the cell in membrane coated vesicles (reviewed in Piddini and Vincent, 2003). The signals can then be released into the cell while the receptor is either recycled to the plasma membrane or down-regulated by its degradation in lysosomes.

By far the most common type of cell signaling is the third class, in which signal transduction occurs via second messengers (the first messenger being the receptor itself). In this form of signal transduction, the ligand binds to its receptor at the cell membrane and induces a change in the receptor conformation. This can cause the clustering of receptor molecules, alteration in enzymatic activity, or a change in the receptorÕs association with internal molecules.

An example of cell signaling by inducing a conformational change is illustrated by ion channel receptors (reviewed in Domene et al., 2003). In this case, signals are transduced across the membrane by the passage of ions through the ion channel. On binding to its ligand, the receptor opens the ion channel. For some receptors, this allows a small transient flux of ions that briefly changes the voltage across the plasma membrane. With other receptors, a massive influx of ions passes through the ion channel to initiate an intracellular response. The first instance occurs primarily in neurons and muscle cells where a change in membrane potential causes a rapid depolarization of the cell membrane leading ultimately neurotransmitter secretion and the propagation of the signal to the succeeding nerve or muscle cells. In the second example, it is usually Ca++ that floods into the cell, causing alterations in intracellular protein conformations and activation of other protein kinases such as protein kinase C (PKC).

Another means of cell signaling is through the activation of various receptor kinases. These enzymes add phosphate groups to proteins on either serine and threonine residues (Biondi and Nebreda, 2003), or on tyrosine residues (Pawson, 2002). In some cases, it is the receptor itself that phosphorylates the intracellular proteins. Some of these receptors include the PDGF-, EGF-, and TGF-β-receptors. In many other situations however, the receptor associates with molecules on the cytoplasmic side of the plasma membrane and upon binding its ligand, causes the activation of the associated proteins. Examples of this include the c-Src- and IL2-receptors. Downstream members of these signaling pathways usually include other kinases such as the cAMP-dependent protein kinase (PKA) and PKC.

G-protein coupled receptors (GPCRs) make up another sub-class of the third group of cell signaling molecules (reviewed in Brink et al., 2004). They constitute a large family of seven-transmembrane spanning receptors that includes the acetylcholinergic and histaminergic receptors. The GPCRs are so named because of their ability to activate G-proteins (GTP-binding proteins). These heterotrimeric proteins consist of α- and β-subunits and in the resting state are not associated with the GPCR. On receptor binding of the ligand, the G-protein associates with the GPCR, leading to the exchange of GTP for GDP on the Gα-subunit. This allows the release of the Gβ-subunit and both Gα- and the GCFα-subunits to their downstream targets (kinases, adenyl cyclase, phospholipase C, etc.) to affect cellular changes. After GTP hydrolysis, the Gβ - and the Gβ-subunits return to their original state.

Comprehending signaling transduction and the crosstalk that exists between the different signaling pathways is an important goal for researchers. A full understanding of these molecules will aid in the prediction of potential drug interactions in clinical settings and can help improve therapeutic strategies for human disease states. While the properties of many of the signaling molecules are well understood, further studies are still required for complete elucidation of this field.

References

1. Beato M and Klug J. (2000) Steroid hormone receptors: an update. Hum. Reprod. Update 6:225-236.
2. Biondi RM and Nebreda AR. (2003) Signaling specificity of Ser/Thr protein kinases though docking site-mediated interactions. Biochem. J. 372:1-13.
3. Brink CB, Harvey BH, Bodenstein J, Venter DP, and Oliver DW. (2004) Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology. Br. J. Clin. Pharmacol. 57:373-387.
4. Domene C, Haidar S, and Sansom MS. (2003) Ion channel structures: a review of recent progress. Curr. Opin. Drug Discov. Devel. 6:611-619.
5. Pawson T. (2002) Regulation and targets of receptor tyrosine kinases. Eur. J. Cancer 38 Suppl 5:S3-10.
6. Piddini E and Vincent JP. (2003) Modulation of developmental signals by endocytosis: different means and many ends. Curr. Opin. Cell Biol. 15:474-481.