Editing Signal transduction (section)

==Stimuli==
{{Main|Stimulus (physiology)}}
[[File:Signal Transduction.jpg|thumb|276x276px|3D Medical animation still showing signal transduction.]]
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 [[epidermal growth factor|EGF]], to intracellular events, such as the DNA damage resulting from [[replicative senescence|replicative]] [[telomere]] attrition.<ref>{{Cite journal |vauthors=Smogorzewska A, de Lange T |date=August 2002 |title=Different telomere damage signaling pathways in human and mouse cells |journal=The EMBO Journal |volume=21 |issue=16 |pages=4338–48 |doi=10.1093/emboj/cdf433 |pmc=126171 |pmid=12169636}}</ref> Traditionally, signals that reach the central nervous system are classified as [[sense]]s. 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.<ref>{{Cite journal |vauthors=Lawrence PA, Levine M |date=April 2006 |title=Mosaic and regulative development: two faces of one coin |journal=Current Biology |volume=16 |issue=7 |pages=R236-9 |doi=10.1016/j.cub.2006.03.016 |pmid=16581495 |doi-access=free}}</ref>

===Ligands===
{{Main|Ligand (biochemistry)}}
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 cytoplasmic or [[nuclear receptors]].<ref name="beato">{{Cite journal |vauthors=Beato M, Chávez S, Truss M |date=April 1996 |title=Transcriptional regulation by steroid hormones |journal=Steroids |volume=61 |issue=4 |pages=240–51 |doi=10.1016/0039-128X(96)00030-X |pmid=8733009 |s2cid=20654561}}</ref> In the case of [[steroid hormone receptor]]s, their stimulation leads to binding to the [[promoter (biology)|promoter region]] of steroid-responsive genes.<ref name="hammes">{{Cite journal |vauthors=Hammes SR |date=March 2003 |title=The further redefining of steroid-mediated signaling |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=100 |issue=5 |pages=2168–70 |bibcode=2003PNAS..100.2168H |doi=10.1073/pnas.0530224100 |pmc=151311 |pmid=12606724 |doi-access=free}}</ref>

Not all classifications of signaling molecules take into account the molecular nature of each class member. For example, [[odorants]] belong to a wide range of molecular classes,<ref name="ronnett">{{Cite journal |vauthors=Ronnett GV, Moon C |year=2002 |title=G proteins and olfactory signal transduction |journal=Annual Review of Physiology |volume=64 |issue=1 |pages=189–222 |doi=10.1146/annurev.physiol.64.082701.102219 |pmid=11826268}}</ref> as do neurotransmitters, which range in size from small molecules such as [[dopamine]]<ref name="missale">{{Cite journal |vauthors=Missale C, Nash SR, Robinson SW, Jaber M, Caron MG |date=January 1998 |title=Dopamine receptors: from structure to function |journal=Physiological Reviews |volume=78 |issue=1 |pages=189–225 |doi=10.1152/physrev.1998.78.1.189 |pmid=9457173}}</ref> to [[neuropeptides]] such as [[endorphins]].<ref name="goldstein">{{Cite journal |vauthors=Goldstein A |date=September 1976 |title=Opioid peptides endorphins in pituitary and brain |journal=Science |volume=193 |issue=4258 |pages=1081–6 |bibcode=1976Sci...193.1081G |doi=10.1126/science.959823 |pmid=959823}}</ref> Moreover, some molecules may fit into more than one class, e.g. [[epinephrine]] is a neurotransmitter when secreted by the [[central nervous system]] and a hormone when secreted by the [[adrenal medulla]].<ref>{{Cite web |date=2011-02-02 |title=https://www.cancer.gov/publications/dictionaries/cancer-terms/def/epinephrine |url=https://www.cancer.gov/publications/dictionaries/cancer-terms/def/epinephrine |access-date=2025-04-24 |website=www.cancer.gov |language=en}}</ref>

Some receptors such as [[HER2]] are capable of '''ligand-independent activation''' when overexpressed or mutated. This leads to constitutive activation of the pathway, which may or may not be overturned by compensation mechanisms. In the case of HER2, which acts as a dimerization partner of other [[ErbB|EGFR]]s, constitutive activation leads to hyperproliferation and [[cancer]].<ref>{{Cite journal |vauthors=Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, etal |date=October 2012 |title=Comprehensive molecular portraits of human breast tumours |journal=Nature |volume=490 |issue=7418 |pages=61–70 |bibcode=2012Natur.490...61T |doi=10.1038/nature11412 |pmc=3465532 |pmid=23000897 |collaboration=The Cancer Genome Atlas Network}}</ref>

===Mechanical forces===
{{Main|Mechanotransduction}}
The prevalence of [[basement membranes]] in the tissues of [[Eumetazoa]]ns means that most cell types require [[cell adhesion|attachment]] to survive. This requirement has led to the development of complex mechanotransduction pathways, allowing cells to sense the stiffness of the substratum. Such signaling is mainly orchestrated in [[focal adhesions]], regions where the [[integrin]]-bound [[actin]] [[cytoskeleton]] detects changes and transmits them downstream through [[YAP1]].<ref>{{Cite journal |display-authors=6 |vauthors=Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S |date=June 2011 |title=Role of YAP/TAZ in mechanotransduction |journal=Nature |volume=474 |issue=7350 |pages=179–83 |doi=10.1038/nature10137 |pmid=21654799 |s2cid=205225137}}</ref> Calcium-dependent [[cell adhesion molecules]] such as [[cadherin]]s and [[selectin]]s can also mediate mechanotransduction.<ref>{{Cite journal |vauthors=Ingber DE |date=May 2006 |title=Cellular mechanotransduction: putting all the pieces together again |journal=FASEB Journal |volume=20 |issue=7 |pages=811–27 |doi=10.1096/fj.05-5424rev |pmid=16675838 |s2cid=21267494 |doi-access=free}}</ref> Specialised forms of mechanotransduction within the nervous system are responsible for [[mechanosensation]]: [[hearing]], [[touch]], [[proprioception]] and [[sense of balance|balance]].<ref>{{Cite journal |vauthors=Kung C |date=August 2005 |title=A possible unifying principle for mechanosensation |journal=Nature |volume=436 |issue=7051 |pages=647–54 |bibcode=2005Natur.436..647K |doi=10.1038/nature03896 |pmid=16079835 |s2cid=4374012}}</ref>

===Osmolarity===
{{Main|Osmoreceptor}}
Cellular and systemic control of [[osmotic pressure]] (the difference in [[osmolarity]] between the [[cytosol]] and the extracellular medium) is critical for homeostasis. There are three ways in which cells can detect osmotic stimuli: as changes in macromolecular crowding, ionic strength, and changes in the properties of the plasma membrane or cytoskeleton (the latter being a form of mechanotransduction).<ref name="Pedersen">{{Cite journal |vauthors=Pedersen SF, Kapus A, Hoffmann EK |date=September 2011 |title=Osmosensory mechanisms in cellular and systemic volume regulation |journal=Journal of the American Society of Nephrology |volume=22 |issue=9 |pages=1587–97 |doi=10.1681/ASN.2010121284 |pmid=21852585 |doi-access=free}}</ref> These changes are detected by proteins known as osmosensors or osmoreceptors. In humans, the best characterised osmosensors are [[transient receptor potential channel]]s present in the [[primary cilium]] of human cells.<ref name="Pedersen" /><ref>{{Cite journal |vauthors=Verbalis JG |date=December 2007 |title=How does the brain sense osmolality? |journal=Journal of the American Society of Nephrology |volume=18 |issue=12 |pages=3056–9 |doi=10.1681/ASN.2007070825 |pmid=18003769 |doi-access=free}}</ref> In yeast, the HOG pathway has been extensively characterised.<ref>{{Cite journal |vauthors=Hohmann S |date=June 2002 |title=Osmotic stress signaling and osmoadaptation in yeasts |journal=Microbiology and Molecular Biology Reviews |volume=66 |issue=2 |pages=300–72 |doi=10.1128/MMBR.66.2.300-372.2002 |pmc=120784 |pmid=12040128}}</ref>

===Temperature===
{{Main|Thermoception}}
The sensing of temperature in cells is known as thermoception and is primarily mediated by [[transient receptor potential channel]]s.<ref name="Sengupta">{{Cite journal |vauthors=Sengupta P, Garrity P |date=April 2013 |title=Sensing temperature |journal=Current Biology |volume=23 |issue=8 |pages=R304-7 |doi=10.1016/j.cub.2013.03.009 |pmc=3685181 |pmid=23618661}}</ref> Additionally, animal cells contain a conserved mechanism to prevent high temperatures from causing cellular damage, the [[heat-shock response]]. Such response is triggered when high temperatures cause the dissociation of inactive [[HSF1]] from complexes with [[heat shock proteins]] [[Hsp40]]/[[Hsp70]] and [[Hsp90]]. With help from the [[ncRNA]] ''hsr1'', HSF1 then trimerizes, becoming active and upregulating the expression of its target genes.<ref>{{Cite journal |vauthors=Shamovsky I, Ivannikov M, Kandel ES, Gershon D, Nudler E |date=March 2006 |title=RNA-mediated response to heat shock in mammalian cells |journal=Nature |volume=440 |issue=7083 |pages=556–60 |bibcode=2006Natur.440..556S |doi=10.1038/nature04518 |pmid=16554823 |s2cid=4311262}}</ref> Many other thermosensory mechanisms exist in both [[prokaryotes]] and [[eukaryotes]].<ref name="Sengupta" />

===Light===
{{Main|Visual phototransduction}}
In mammals, [[light]] controls the sense of [[Visual perception|sight]] and the [[circadian clock]] by activating light-sensitive proteins in [[photoreceptor cell]]s in the [[eye]]'s [[retina]]. In the case of vision, light is detected by [[rhodopsin]] in [[rod cells|rod]] and [[cone cells]].<ref name="burns">{{Cite journal |vauthors=Burns ME, Arshavsky VY |date=November 2005 |title=Beyond counting photons: trials and trends in vertebrate visual transduction |journal=Neuron |volume=48 |issue=3 |pages=387–401 |doi=10.1016/j.neuron.2005.10.014 |pmid=16269358 |doi-access=free}}</ref> In the case of the circadian clock, a different [[photopigment]], [[melanopsin]], is responsible for detecting light in [[intrinsically photosensitive retinal ganglion cells]].<ref>{{Cite journal |vauthors=Berson DM |date=August 2007 |title=Phototransduction in ganglion-cell photoreceptors |journal=Pflügers Archiv |volume=454 |issue=5 |pages=849–55 |doi=10.1007/s00424-007-0242-2 |pmid=17351786 |doi-access=free}}</ref>