Signal+Transduction

3) Signal Transduction

// a. Give a basic description of the technique/process/concept. Feel free to include // // figures/diagrams/flowcharts. //

In order for an organism to function, its cells must first be able to work together to carry out the day-to-day processes that enable life. Such cell-to-cell communication involves not only the transmission of chemical signals across the space between one cell and another, but also complex intracellular mechanisms. These mechanisms are necessary in timing the emission of signals and enabling the interpretation of the signals by the receptor cells. Only after interpretation can cell signals be translated into physiological processes. Cells require extracellular signal molecules to communicate over both long and short distances. Cells in multicellular animals communicate by means of hundreds of kinds of signal molecules. These include proteins, small peptides, amino acids, nucleoacids, steroids, retinoids, fatty acid derivatives, and even dissolved gases. During the communication process, these molecules are emitted through one of four primary ways- while most are released into the extracellular space by exocytosis, others, called transmembrane proteins, may be displayed on the external surface of the cell as signals that respond to physical contact. Transmembrane proteins may also release their extracellular domains through proteolytic cleavage and act at a distance. Lastly, some signal molecules simply diffuse through the plasma membrane into the extracellular space, free to react with neighboring signals. In all of these cases, another factor is needed to complete the process of cell signaling- the target cell. Acting through a receptor, the target cell is acted upon by various intracellular signals that ultimately end up altering it’s behavior. Receptors, most often composed of transmembrane proteins, have a predisposed high affinity for the signal molecules they receive. In some cases, however, the receptor proteins can also be inside the cell. In order to bind to them then, correlating signal molecules must first enter the cell through diffusion across the target cell’s plasma membrane. Unfortunately though, very few molecules are able to diffuse through the membrane. Most signal molecules besides a few nonpolar signal molecules such as estrogens and other steroid hormones are too polar and too large to pass through, and no appropriate transport systems are present. Thus, the information that signal molecules transmit must be communicated through the membrane without the signal molecules themselves entering the cell. Very specific proteins called membrane-associated receptor proteins fill this need and aid the cell in transferring the signal molecule’s information across the membrane. Only when a second messenger transmits the signal into the cell itself does the end-goal physiological chance take place. The second messenger system is known as signal transduction. [1][6]

// b. What is the purpose of the technique/process/concept within cell biology? What function/benefit can it provide? //

Signal transduction is essential to cell biology because it is the method by which cellular signals are amplified. When a chemical signal binds to the outer region of a cell membrane protein receptor, the receptor undergoes a conformation change. The change causes the proliferation of another signal inside the cell, and the process repeats. With each additional step, the signal that is being transduced amplifies- thereby enabling once small signals to be translated into large responses. This process is called a signal-transduction cascade, and it is in charge of mediating the sensing and processing of stimuli. These molecular circuits detect external signals and then integrate them into amplified responses such as enzyme activity, gene expression, or ion-channel activity. Feedback pathways regulate the entire signaling process. [1][6]

// c. Describe one disease specifically associated with, or studied using, this technique/process/concept. //

Research in the past has linked a range of diseases to improper signal transduction, with one in particular being congestive heart failure. Altered signal transduction mechanisms can result in the loss of contractility, leading to heart failure. For example, impairment of the Gs-Protein and Gi-Protein transduction chains can lead to decreased contractility. When the B1-adrenoceptor and the Gs-protein are uncoupled, there is a reduced ability to activate adenylyl cyclase, which is essential to the phosphorylation of L-type calcium channels. When this process is impaired, calcium influx into the cells is reduces, and the sarcoplasmic reticulum begins to release less calcium. The excitation-contraction coupling is then impaired, which directly affects contractility. [2][3]

// d. Are there any key individuals identified in the original research that lead to the current accepted theories/model describing this technique/process/concept? //

Historically, the earliest identifier of signal transduction was Martin Rodbell in 1970, a scientist that examined the effects of glucagon on a rat’s liver cell membrane receptor. By identifying that G-protein accepted glucagon molecules and then affected the cell, he deduced the first transducer. Signal transduction was not used to describe such processes until later on in 1972 and onwards. [7]

// e. Choose three research articles (from after 2009) that discuss the process. Explain the importance of results/analysis in each paper that led to a greater understanding of this process. What important fact(s)/idea(s) did the paper/research reveal? //

= Regulation of cross-talk in yeast MAPK signaling pathways  = Signal transduction is a large and complicated process that is essential to the successful communication of information throughout an organism. Because many signal proteins are part of large, comparable families that are similar structurally, the chances of cross talk, or one signaling pathway inferring with another, is high. This study explored the mechanisms that yeast employs to hinder cross talk between MAP kinase pathways and to insulate and specify the pathways. This paper concluded that prevention of cross talk is not regulated by a single mechanism, but by a combination of many including docking interactions, scaffold proteins, cross-pathway inhibition, and kinetic insulation. These factors work in conjunction with one another within yeast to prevent the three MAPK pathways (pheromone response, filamentous growth response and osmostress adaptation) from interfering with one another. [5]

= Evolution and phyletic distribution of two-component signal transduction systems Bone morphogenetic protein receptors and signal transduction  = In prokaryotes, signal transduction is a process governed by two-component systems in which a histidine protein kinase and a response regulator protein together activate a response. The histidine is regulated by environmental stimuli and serves to create a high-energy phosphoryl group that goes on to an aspartate residue in the response regulator protein. The regulatory protein then undergoes a conformational change that ultimately leads to an activation of the associated domain and a physiological response. This paper studied the evolution of said two-component signal transduction systems, and investigated their beginnings as one-component systems. The development enabled early organisms to move from intracellular sensing to extracellular sensing, thereby giving them the advantage of detecting signals without making their membranes highly permeable. [8]

= Bone morphogenetic protein receptors and signal transduction  = Besides heart failure, distresses in signal transduction pathways can also cause various clinical disorders and cancer. This paper explored the ramifications of altercations to cone morphogenetic protein pathways that function through signal transduction, and how the various mechanisms involved can lead to the development of cancer. Bone morphogenetic proteins (BMPs) are active in various tissues throughout the body, and are important in the binding of type I and II serine-threonine kinase receptors. If the signaling pathway is disturbed, the signals cannot be communicated through Smad and non-Smad signaling pathways as they normally do. The researchers in this paper proposed that inhibition of the BMP receptors would reduce hyperactivation of the BMPH signaling pathways, and that administration of recombinant BMP ligands and an increase in the expression of BMPs would prove therapeutic to a host of diseases. [4]

References [1] Berg, J. M., Tymoczko, J. L., & Stryer, L. (2002). Signal-Transduction Pathways: An Introduction to Information Metabolism. //Biochemistry// (5th ed., p. None listed). New York: W.H. Freeman. [2] Cardiac Signal Transduction Mechanisms (G-Protein-Linked). (2013, October 25). //Cardiovascular Physiology//. Retrieved November 25, 2013, from http://cvphysiology.com/Blood%20Pressure/BP011a.htm [3] Kawaguchi, H., & Kitabatake, A. (1996). Altered Signal Transduction System In Hypertrophiedmyocardium: Angiotensin II Stimulates Collagen Synthesis In Hypertrophied Hearts. //Journal of Cardiac Failure//, //2//, S13-S19. Retrieved November 26, 2013, from http://dx.doi.org/10.1016/S1071-9164(96)80054-6 [4] Miyazono, K. (1999). Bone morphogenetic protein receptors and signal transduction. //The Journal of Biochemistry//, //147//(1), 35-51. Retrieved November 26, 2013, from http://jb.oxfordjournals.org/content/147/1/35.short [5] Saito, H. (2010). Regulation Of Cross-talk In Yeast MAPK Signaling Pathways. //Current Opinion in Microbiology//, //13//(6), 677-683. Retrieved November 24, 2013, from http://dx.doi.org/10.1016/j.mib.2010.09.001 [6] Shalizi, C. R. (2013, June 19). Signal Transduction, Control of Metabolism, and Gene Regulation. //Signal Transduction, Control of Metabolism, and Gene Regulation//. Retrieved October 30, 2013, from http://vserver1.cscs.lsa.umich.edu/~crshalizi/notebooks/signal-transduction.html [7] The Martin Rodbell Papers. (n.d.). //Profiles in Science//. Retrieved November 27, 2013, from http://profiles.nlm.nih.gov/ps/retrieve/Collection/CID/GG [8] Wuichet, K., Cantwell, B. J., & Zhulin, I. B. (2010). Evolution And Phyletic Distribution Of Two-component Signal Transduction Systems. //Current Opinion in Microbiology//, //13//(2), 219-225. Retrieved November 24, 2013, from http://dx.doi.org/10.1016/j.mib.2009.12.011