Signal Transduction

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response.

Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used.[1] The changes elicited by ligand binding (or signal sensing) in a receptor give rise to a signaling cascade, which is a chain of biochemical events along a signaling pathway. 

When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated, often by combinatorial signaling events.[2] 

At the molecular level, such responses include changes in the transcription or translation of genes, and post-translational and conformational changes in proteins, as well as changes in their location. 

These molecular events are the basic mechanisms controlling cell growth, proliferation, metabolism and many other processes.[3] In multicellular organisms, signal transduction pathways have evolved to regulate cell communication in a wide variety of ways.

Each component (or node) of a signaling pathway is classified according to the role it plays with respect to the initial stimulus. Ligands are termed first messengers, while receptors are the signal transducers, which then activate primary effectors. Such effectors are often linked to second messengers, which can activate secondary effectors, and so on. 

Depending on the efficiency of the nodes, a signal can be amplified (a concept known as signal gain), so that one signaling molecule can generate a response involving hundreds to millions of molecules.[4] 

As with other signals, the transduction of biological signals is characterised by delay, noise, signal feedback and feedforward and interference, which can range from negligible to pathological.[5] 

With the advent of computational biology, the analysis of signaling pathways and networks has become an essential tool to understand cellular functions and disease, including, but not limited to signaling rewiring mechanisms underlying responses to acquired drug resistance (eg, cancer drugs, antiobiotic resistance).[6]

The basis for signal transduction is the transformation of a certain stimulus into a biochemical signal. The nature of such stimuli can vary widely, ranging from extracellular cues, such as the presence of EGF, to intracellular events, such as the DNA damage resulting from replicative telomere attrition.[7] For example, the shortening of telomeres via oxidative stress can trigger the emergence of senescent cells (See the Institute’s take on cellular senescence).

Signals that reach the central nervous system are still classified as senses. These are transmitted from neuron to neuron in a process called synaptic transmission. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development.[8]

Ligands

The majority of signal transduction pathways involve the binding of signaling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signaling molecule with a receptor causes a change in the conformation of the receptor, known as receptor activation. Most ligands are soluble molecules from the extracellular medium which bind to cell surface receptors. These include growth factors, cytokines and neurotransmitters. Components of the extracellular matrix such as fibronectin and hyaluronan can also bind to such receptors (integrins and CD44, respectively). In addition, some molecules such as steroid hormones are lipid-soluble and thus cross the plasma membrane to reach nuclear receptors.[9] In the case of steroid hormone receptors, their stimulation leads to binding to the promoter region of steroid-responsive genes.[10]

Intracellular receptors

Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are non-polar hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, altering gene expression.

Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors of gene expression.

All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor.

Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus.

Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol. In the absence of steroids, they associate in an aporeceptor complex containing chaperone or heatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden. Receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk.

Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a precursor like retinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs. They repress their gene by binding to their specific DNA sequence when no ligand binds to them, and vice versa.

Ligand-gated ion channels

A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to the opening of these channels induces action potentials, such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.

An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it acts as a second messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the synapse.

Nitric oxide

Nitric oxide (NO) acts as a second messenger because it is a free radical that can diffuse through the plasma membrane and affect nearby cells. It is synthesised from arginine and oxygen by the NO synthase and works through activation of soluble guanylyl cyclase, which when activated produces another second messenger, cGMP. NO can also act through covalent modification of proteins or their metal co-factors; some have a redox mechanism and are reversible. It is toxic in high concentrations and causes damage during stroke, but is the cause of many other functions like relaxation of blood vessels, apoptosis, and penile erections.

Redox signaling

In addition to nitric oxide, other electronically activated species are also signal-transducing agents in a process called redox signaling. Examples include, but are not limited to superoxide, hydrogen peroxide, carbon monoxide, and hydrogen sulfide. Redox signaling also includes active modulation of electronic flows in semiconductive biological macromolecules. (11)

An Illustration of a signal transduction pathway

Following is a  signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses. The MAPK/ERK pathway: A pathway that couples intracellular responses to the binding of growth factors to cell surface receptors.  This pathway is very complex and includes many protein components. (12)  In many cell types, activation of this pathway promotes cell division, and many forms of cancer are associated with aberrations therein. (13)

Conclusion

The earliest notion of signal transduction can be traced back to 1855, when Claude Bernard proposed that ductless glands such as the spleen, the thyroid and adrenal glands, were responsible for the release of “internal secretions” with physiological effects. (14-16) Bernard’s “secretions” were later named “hormones” by Ernest Starling in 1905.(16). Together with William Bayliss, Starling had discovered secretin in 1902. (14-16) 

References

  1. ^ Bradshaw, Ralph A.; Dennis, Edward A., eds. (2010). Handbook of Cell Signaling (2nd ed.). Amsterdam, Netherlands: Academic Press. ISBN 9780123741455.
  2. ^ Papin, Jason A.; Hunter, Tony; Palsson, Bernhard O.; Subramaniam, Shankar (14 January 2005). “Reconstruction of cellular signalling networks and analysis of their properties”. Nature Reviews Molecular Cell Biology. 6 (2): 99–111. doi:10.1038/nrm1570. PMID 15654321.
  3. ^ Krauss, Gerhard (2008). Biochemistry of Signal Transduction and Regulation. Wiley-VCH. p. 15. ISBN 978-3527313976.
  4. ^ Reece, Jane; Campbell, Neil (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.
  5. ^ Kolch, Walter; Halasz, Melinda; Granovskaya, Marina; Kholodenko, Boris N. (20 August 2015). “The dynamic control of signal transduction networks in cancer cells”. Nature Reviews Cancer. 15 (9): 515–527. doi:10.1038/nrc3983. PMID 26289315.
  6. ^ Bago R, Sommer E, Castel P, Crafter C, Bailey FP, Shpiro N, Baselga J, Cross D, Eyers PA, Alessi DR (2016) The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. EMBO Journal 35:1902-22
  7. ^ Smogorzewska, A. (15 August 2002). “Different telomere damage signaling pathways in human and mouse cells”. The EMBO Journal. 21 (16): 4338–4348. doi:10.1093/emboj/cdf433. PMC 126171.
  8. ^ Lawrence, Peter A.; Levine, Michael (April 2006). “Mosaic and regulative development: two faces of one coin”. Current Biology. 16 (7): R236–R239. doi:10.1016/j.cub.2006.03.016. PMID 16581495.
  9. ^ Beato M, Chávez S, Truss M (Apr 1996). “Transcriptional regulation by steroid hormones”. Steroids. 61 (4): 240–251. doi:10.1016/0039-128X(96)00030-X. PMID 8733009.
  10. ^ Hammes SR (Mar 2003). “The further redefining of steroid-mediated signaling”. Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2168–70. Bibcode:2003PNAS..100.2168H. doi:10.1073/pnas.0530224100. PMC 151311. PMID 12606724.

(11) Forman, H.J., Signal transduction and reactive species. Free Radic. Biol. Med. 47:1237-1238; 2009

(12).  Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W (Dec 2005). “Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway”. The Biochemical Journal. 392 (Pt 2): 249–61. doi:10.1042/BJ20050908. PMC 1316260. PMID 16293107.

(13) Vogelstein B, Kinzler KW (Aug 2004). “Cancer genes and the pathways they control”. Nature Medicine. 10 (8): 789–99. doi:10.1038/nm1087. PMID 15286780.

(14)   Alberts B, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1

(15). Op cit.,  Bradshaw & Dennis (2010) p.1.

(16). Tata, Jamshed R. (June 2005). “One hundred years of hormones”. EMBO Reports. 6 (6): 490–496. doi:10.1038/sj.embor.7400444. PMC 1369102. PMID 15940278.

 

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