Editing Signal transduction (section)

==History==
[[Image:Signal transduction publications graph.jpeg|400px|thumb|right|Occurrence of the term "signal transduction" in [[MEDLINE]]-indexed papers since 1977]]
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 gland|thyroid]] and [[adrenal gland]]s, were responsible for the release of "internal secretions" with physiological effects.<ref name="HCB1">Bradshaw & Dennis (2010) p. 1.</ref> Bernard's "secretions" were later named "[[hormones]]" by [[Ernest Starling]] in 1905.<ref>{{Cite journal |vauthors=Tata JR |date=June 2005 |title=One hundred years of hormones |journal=EMBO Reports |volume=6 |issue=6 |pages=490–6 |doi=10.1038/sj.embor.7400444 |pmc=1369102 |pmid=15940278}}</ref> Together with [[William Bayliss]], Starling had discovered [[secretin]] in 1902.<ref name="HCB1" /> Although many other hormones, most notably [[insulin]], were discovered in the following years, the mechanisms remained largely unknown.

The discovery of [[nerve growth factor]] by [[Rita Levi-Montalcini]] in 1954, and [[epidermal growth factor]] by [[Stanley Cohen (biochemist)|Stanley Cohen]] in 1962, led to more detailed insights into the molecular basis of cell signaling, in particular [[growth factor]]s.<ref>{{Cite journal |vauthors=Cowan WM |date=March 2001 |title=Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor |journal=Annual Review of Neuroscience |volume=24 |issue=1 |pages=551–600 |doi=10.1146/annurev.neuro.24.1.551 |pmid=11283321 |s2cid=6747529}}</ref> Their work, together with [[Earl Wilbur Sutherland]]'s discovery of [[cyclic AMP]] in 1956, prompted the redefinition of [[endocrine signaling]] to include only signaling from glands, while the terms [[autocrine]] and [[paracrine]] began to be used.<ref name="HCB2">Bradshaw & Dennis (2010) p. 2.</ref> Sutherland was awarded the 1971 [[Nobel Prize in Physiology or Medicine]], while Levi-Montalcini and Cohen shared it in 1986.

In 1970, [[Martin Rodbell]] examined the effects of [[glucagon]] on a rat's liver cell membrane receptor. He noted that [[guanosine triphosphate]] disassociated glucagon from this receptor and stimulated the [[G-protein]], which strongly influenced the cell's metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell.<ref name="rodbell">{{Cite journal |vauthors=Rodbell M |date=March 1980 |title=The role of hormone receptors and GTP-regulatory proteins in membrane transduction |journal=Nature |volume=284 |issue=5751 |pages=17–22 |bibcode=1980Natur.284...17R |doi=10.1038/284017a0 |pmid=6101906 |s2cid=5650340}}</ref> For this, he shared the 1994 [[Nobel Prize in Physiology or Medicine]] with [[Alfred G. Gilman]]. Thus, the characterization of RTKs and GPCRs led to the formulation of the concept of "signal transduction", a word first used in 1972.<ref name="rensing">{{Cite journal |vauthors=Rensing L |year=1972 |title=Periodic geophysical and biological signals as Zeitgeber and exogenous inducers in animal organisms |journal=International Journal of Biometeorology |volume=16 Suppl |pages=113–25 |pmid=4621276}}</ref> Some early articles used the terms ''signal transmission'' and ''sensory transduction''.<ref name="tonndorf">{{Cite journal |vauthors=Tonndorf J |date=September 1975 |title=Davis-1961 revisited. Signal transmission in the cochlear hair cell-nerve junction |journal=Archives of Otolaryngology |volume=101 |issue=9 |pages=528–35 |doi=10.1001/archotol.1975.00780380006002 |pmid=169771}}</ref><ref name="ashcroft">{{Cite journal |vauthors=Ashcroft SJ, Crossley JR, Crossley PC |date=March 1976 |title=The effect of N-acylglucosamines on the biosynthesis and secretion of insulin in the rat |journal=The Biochemical Journal |volume=154 |issue=3 |pages=701–7 |doi=10.1042/bj1540701 |pmc=1172772 |pmid=782447}}</ref> In 2007, a total of 48,377 scientific papers—including 11,211 [[review journal|review papers]]—were published on the subject. The term first appeared in a paper's title in 1979.<ref name="hildebrand">{{Cite journal |vauthors=Hildebrand E |date=April 1977 |title=What does Halobacterium tell us about photoreception? |journal=Biophysics of Structure and Mechanism |volume=3 |issue=1 |pages=69–77 |doi=10.1007/BF00536457 |pmid=857951 |s2cid=62775788}}</ref><ref name="kenny">{{Cite journal |vauthors=Kenny JJ, Martínez-Maza O, Fehniger T, Ashman RF |date=April 1979 |title=Lipid synthesis: an indicator of antigen-induced signal transduction in antigen-binding cells |journal=Journal of Immunology |volume=122 |issue=4 |pages=1278–84 |doi=10.4049/jimmunol.122.4.1278 |pmid=376714 |s2cid=29355685 |doi-access=free}}</ref> Widespread use of the term has been traced to a 1980 review article by Rodbell:<ref name=rodbell/><ref name="gomperts">{{Cite book |title=Signal transduction |vauthors=Gomperts BD, Kramer IM, Tatham PE |publisher=Academic Press |year=2002 |isbn=978-0-12-289631-6}}</ref> Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s.<ref name="Vander_1998">{{Cite book |last=Vander |first=Arthur J |title=Human Physiology |last2=Sherman |first2=James |last3=Luciano |first3=Dorothy |publisher=McGraw-Hill |year=1998 |isbn=978-0-07-067065-5 |edition=7th |pages=159–60 |name-list-style=vanc}}</ref>

===Signal transduction in [[Immunology]]===
The purpose of this section is to briefly describe some developments in immunology in the 1960s and 1970s, relevant to the initial stages of transmembrane signal transduction, and how they impacted our understanding of immunology, and ultimately of other areas of cell biology.

The relevant events begin with the sequencing of [[myeloma protein]] light chains, which are found in abundance in the urine of individuals with [[multiple myeloma]].  Biochemical experiments revealed that these so-called Bence Jones proteins consisted of 2 discrete domains –one that varied from one molecule to the next (the V domain) and one that did not (the Fc domain or the [[Fragment crystallizable region]]).<ref>Steiner, L A (1996)  Immunoglobulin evolution, 30 years on. Glycobiology  6 , 649-656</ref>  An analysis of multiple V region sequences by  Wu and Kabat <ref>Wu, T T, Kabat, E  A  (1970) An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J. Exp. Med. 132: 211-250</ref> identified locations within the V region that were hypervariable and which, they hypothesized, combined in the folded protein to form the  antigen recognition site. Thus, within a relatively short time a plausible model was developed for the molecular basis of immunological specificity, and for mediation of  biological function through the Fc domain. Crystallization of an IgG molecule soon followed <ref>Sarma, V R, Silverton, E W,  Davies, D R, Terry W D (1971) The three-dimensional structure at 6 A resolution of a human gamma G1 immunoglobulin molecule, J Biol. Chem. 246  (11) 3752- 9</ref> ) confirming the inferences based on sequencing, and providing an understanding of immunological specificity at the highest level of resolution.

The biological significance of these developments was encapsulated in the theory of [[clonal selection]]<ref>Burnet, F M (1976) A modification of Jerne's theory of antibody production using the concept of clonal selection. CA: A Cancer Journal for Clinicians 26 (2) 119–21</ref> which holds that a [[B cell]] has on its surface immunoglobulin receptors whose antigen-binding site is identical to that of antibodies that are secreted by the cell when it encounters an antigen, and more specifically a particular  B cell clone secretes antibodies with identical sequences.  The final piece of the story, the [[Fluid mosaic model]]  of the plasma membrane provided all the ingredients for a new model for the initiation of signal transduction; viz, receptor dimerization.

The first hints of this were obtained by Becker et al  <ref>Becker, K E, Ishizaka, T, Metzger, H, Ishizaka, K and Grimley, P M (1973)  Surface IgE on Human Basophils during histamine release. J Exp med, 138, 394-408</ref> who demonstrated that the extent to which human [[basophils]]—for which bivalent [[Immunoglobulin E]] (IgE)  functions as a surface receptor – degranulate, depends on the concentration of anti IgE antibodies to which they are exposed, and results in a redistribution of surface molecules, which is absent when monovalent [[ligand]] is used. The latter observation was consistent with earlier findings by Fanger et al.<ref>Fanger, M W, Hart, D A, Wells, J V, and Nisonoff, A J (1970) Requirement for cross-linkage in the stimulation of transformation of rabbit peripheral lymphocytes by antiglobulin reagents  J. Immun., 105, 1484 - 92</ref> These observations tied a biological response to events and structural details of molecules on the cell surface. A preponderance of evidence soon developed that receptor dimerization initiates responses (reviewed in  <ref>Klemm J D,  Schreiber S L, Crabtree G R (1998) Ann. Rev. Immunol.  Dimerization as a regulatory mechanism in signal transduction 16: 569-592</ref>) in a variety of cell types, including B cells.

Such observations led to a number of theoretical (mathematical) developments. The first of these was a simple model proposed by Bell  <ref>Bell, G I (1974) Model for the binding of multivalent antigens to cells, Nature Lond. 248, 430</ref> which resolved an apparent paradox: clustering forms stable networks; i.e. binding is essentially irreversible, whereas the affinities of antibodies secreted by B cells increase as the immune response progresses.  A theory of the dynamics of cell surface clustering on lymphocyte membranes was developed by [[DeLisi]] and Perelson <ref>DeLisi, C and Perelson A (1976). The kinetics of aggregation phenomena, J. theor. Biol.  62, 159-210</ref> who found the size distribution of clusters as a function of time, and its dependence on the affinity and valence of the ligand.  Subsequent theories for basophils and mast cells were developed by Goldstein and Sobotka and their collaborators,<ref>Dembo, M and  Goldstein, B (1978) Theory of equilibrium binding of symmetric bivalent haptens to cell surface antibody: application to histamine release from basophils. The Journal of Immunology 121 (1), 345-353</ref><ref>Sobotka, A.K.  Dembo, M, Goldstein, B and  Lichtenstein, L M, (1979) Antigen-specific desensitization of human basophils The Journal of Immunology, 122  (2) 511-517</ref> all aimed at the analysis of dose-response patterns of immune cells and their biological correlates.<ref>Kagey-Sobotka, A,  Dembo, M,  Goldstein, B, Metzger, H and  Lichtenstein, L M (1981) Qualitative characteristics of histamine release from human basophils by covalently cross-linked IgE. The Journal of Immunology 127 (6), 2285-2291</ref> For a recent review of clustering in immunological systems see.<ref>How does T cell receptor clustering impact signal transduction? Jesse Goyette, Daniel J. Nieves, Yuanqing Ma, Katharina Gaus Journal of Cell Science 2019 132:jcs226423 {{doi|10.1242/jcs.226423}} Published 11 February 2019</ref>

Ligand binding to cell surface receptors is also critical to motility, a phenomenon that is best understood in single-celled organisms. An example is a detection and response to concentration gradients by bacteria <ref>MacNab, R., and D. E. Koshland, Jr. (1972). The gradient-sensing mechanism in bacterial chemotaxis. Proc. Natl. Acad. Sci. U.S.A. 69:2509-2512</ref>-–the classic mathematical theory appearing in.<ref>Berg, H C and Purcell, E M (1977) Physics of chemoreception, Biophys. J  20(2):193-219</ref> A recent account can be found in <ref>Kirsten Jung, Florian Fabiani, Elisabeth Hoyer, and Jürgen Lassak  2018 Bacterial transmembrane signaling systems and their engineering for biosensing Open Biol. Apr; 8(4): 180023</ref>