Editing Paracrine signaling

{{short description|Form of localized cell signaling}}

In [[cellular biology]], '''paracrine signaling''' is a form of [[cell signaling]], a type of [[cellular communication (biology)|cellular communication]] in which a [[Cell (biology)|cell]] produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as '''paracrine factors''' [[diffuse]] over a relatively short distance (local action), as opposed to cell signaling by [[endocrine system|endocrine factors]], [[hormone]]s which travel considerably longer distances via the [[circulatory system]]; [[juxtacrine signaling|juxtacrine interactions]]; and [[autocrine signaling]]. Cells that produce paracrine factors secrete them into the immediate [[extracellular]] environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

[[File:signal transduction pathways.png|thumb|500px|right|Overview of signal transduction pathways.]]

Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of [[Receptor (biochemistry)|receptor]]s and pathways. In fact, different [[organ (biology)|organ]]s in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development.<ref>{{cite web|title=Paracrine Factors|url=https://www.ncbi.nlm.nih.gov/books/NBK10071/|access-date=27 July 2018}}</ref> The highly conserved receptors and pathways can be organized into four major families based on similar structures:  [[fibroblast growth factor]] (FGF) family, [[Hedgehog signaling pathway|Hedgehog]] family, [[Wnt signaling pathway|Wnt]] family, and [[Transforming growth factor beta|TGF-β superfamily]]. Binding of a paracrine factor to its respective receptor initiates [[signal transduction]] cascades, eliciting different responses.

==Paracrine factors induce competent responders==
In order for paracrine factors to successfully induce a response in the receiving cell, that cell must have the appropriate receptors available on the cell membrane to receive the signals, also known as being [[natural competence|competent]]. Additionally, the responding cell must also have the ability to be mechanistically induced.

==Fibroblast growth factor (FGF) family==
Although the FGF family of paracrine factors has a broad range of functions, major findings support the idea that they primarily stimulate proliferation and differentiation.<ref name="Gospodarowicz">{{cite journal |doi=10.1210/edrv-8-2-95 |title=Structural Characterization and Biological Functions of Fibroblast Growth Factor |year=1987 |last1=Gospodarowicz |first1=D. |last2=Ferrara |first2=N. |last3=Schweigerer |first3=L. |last4=Neufeld |first4=G. |journal=Endocrine Reviews |volume=8 |issue=2 |pages=95–114 |pmid=2440668}}</ref><ref name="Rifkin">{{cite journal |first1=Daniel B. |last1=Rifkin |first2=David |last2=Moscatelli |pmid=2545723 |jstor=1613457 |year=1989 |title=Recent developments in the cell biology of basic fibroblast growth factor |volume=109 |issue=1 |pages=1–6 |pmc=2115467 |journal=The Journal of Cell Biology |doi=10.1083/jcb.109.1.1}}</ref> To fulfill many diverse functions, FGFs can be alternatively spliced or even have different initiation codons to create hundreds of different FGF [[isoforms]].<ref name="Lappi">{{cite journal |doi=10.1006/scbi.1995.0036 |title=Tumor targeting through fibroblast growth factor receptors |year=1995 |last1=Lappi |first1=Douglas A. |journal=Seminars in Cancer Biology |volume=6 |issue=5 |pages=279–88 |pmid=8562905}}</ref>

One of the most important functions of the FGF receptors (FGFR) is in limb development. This signaling involves nine different [[alternatively spliced]] [[isoforms]] of the receptor.<ref name="Ornitz">{{cite journal |doi=10.1074/jbc.271.25.15292 |title=Receptor Specificity of the Fibroblast Growth Factor Family |year=1996 |last1=Xu |first1=J. |journal=Journal of Biological Chemistry |volume=271 |issue=25 |pages=15292–7 |pmid=8663044 |last2=Xu |first2=J |last3=Colvin |first3=JS |last4=McEwen |first4=DG |last5=MacArthur |first5=CA |last6=Coulier |first6=F |last7=Gao |first7=G |last8=Goldfarb |first8=M|doi-access=free }}</ref> ''Fgf''8 and ''Fgf''10 are two of the critical players in limb development. In the forelimb initiation and limb growth in mice, axial (lengthwise) cues from the intermediate [[mesoderm]] produces ''Tbx''5, which subsequently signals to the same [[mesoderm]] to produce ''Fgf''10. ''Fgf''10 then signals to the [[ectoderm]] to begin production of ''Fgf''8, which also stimulates the production of ''Fgf''10.  Deletion of ''Fgf''10 results in limbless mice.<ref name="Logan">{{cite journal |doi=10.1242/dev.00956 |title=Finger or toe: The molecular basis of limb identity |year=2003 |last1=Logan |first1=M. |journal=Development |volume=130 |issue=26 |pages=6401–10 |pmid=14660539|doi-access=free }}</ref>

Additionally, paracrine signaling of Fgf is essential in the developing eye of chicks. The ''fgf''8 [[mRNA]] becomes localized in what differentiates into the neural [[retina]] of the [[optic cup (embryology)|optic cup]]. These cells are in contact with the outer ectoderm cells, which will eventually become the lens.<ref name="Lappi" />

[[Phenotype]] and survival of mice after knockout of some FGFR genes:<ref name="Ornitz" />
{| class="wikitable"
|-
! FGFR Knockout Gene !! Survival !! Phenotype
|-
| ''Fgf''1|| Viable|| Unclear
|-
| ''Fgf''3|| Viable|| Inner ear, skeletal (tail) differentiation
|-
| ''Fgf''4|| Lethal|| Inner cell mass proliferation 
|-
| ''Fgf''8|| Lethal|| [[Gastrulation]] defect, CNS development, limb development 
|-
| ''Fgf''10|| Lethal|| Development of multiple organs (including limbs, thymus, pituitary)
|-
| ''Fgf''17|| Viable|| Cerebellar Development 
|}

===Receptor tyrosine kinase (RTK) pathway===
Paracrine signaling through [[fibroblast growth factors]] and its respective receptors utilizes the receptor [[tyrosine]] pathway.  This signaling pathway has been highly studied, using ''Drosophila'' eyes and human cancers.<ref name="Fantl,">{{cite journal |doi=10.1146/annurev.bi.62.070193.002321 |title=Signaling by Receptor Tyrosine Kinases |year=1993 |last1=Fantl |first1=Wendy J |last2=Johnson |first2=Daniel E |last3=Williams |first3=Lewis T |journal=Annual Review of Biochemistry |volume=62 |pages=453–81 |pmid=7688944}}</ref>

Binding of FGF to FGFR [[phosphorylates]] the idle [[kinase]] and activates the RTK pathway.  This pathway begins at the cell membrane surface, where a [[ligand]] binds to its specific receptor.  Ligands that bind to RTKs include [[fibroblast growth factors]], epidermal growth factors, platelet-derived growth factors, and [[stem cell factor]].<ref name="Fantl," />  This dimerizes the transmembrane receptor to another RTK receptor, which causes the autophosphorylation and subsequent [[conformational change]] of the [[homodimer]]ized receptor.  This conformational change activates the dormant kinase of each RTK on the tyrosine residue.  Due to the fact that the receptor spans across the membrane from the extracellular environment, through the [[lipid bilayer]], and into the [[cytoplasm]], the binding of the receptor to the ligand also causes the trans phosphorylation of the cytoplasmic domain of the receptor.<ref name="Yarden,">{{cite journal |doi=10.1146/annurev.bi.57.070188.002303 |title=Growth Factor Receptor Tyrosine Kinases |year=1988 |last1=Yarden |first1=Yosef |last2=Ullrich |first2=Axel |journal=Annual Review of Biochemistry |volume=57 |pages=443–78 |pmid=3052279}}</ref>

An [[Signal transducing adaptor protein|adaptor protein]] (such as SOS) recognizes the phosphorylated tyrosine on the receptor.  This protein functions as a bridge which connects the RTK to an intermediate protein (such as GNRP), starting the intracellular signaling cascade.  In turn, the intermediate protein stimulates GDP-bound Ras to the activated GTP-bound Ras.  GAP eventually returns Ras to its inactive state.  Activation of [[Ras subfamily|Ras]] has the potential to initiate three signaling pathways downstream of Ras: Ras→Raf→MAP kinase pathway, PI3 kinase pathway, and Ral pathway.  Each pathway leads to the activation of transcription factors which enter the nucleus to alter gene expression.<ref name="Katz,">{{cite journal |doi=10.1016/S0959-437X(97)80112-8 |title=Signal transduction from multiple Ras effectors |year=1997 |last1=Katz |first1=Michael E |last2=McCormick |first2=Frank |journal=Current Opinion in Genetics & Development |volume=7 |pages=75–9 |pmid=9024640 |issue=1}}</ref>

[[File:MAPKpathway diagram.svg|thumb|right| Diagram showing key components of a signal transduction pathway.  See the [[MAPK/ERK pathway]] article for details.]]

====RTK receptor and cancer====
Paracrine signaling of growth factors between nearby cells has been shown to exacerbate [[carcinogenesis]].  In fact, mutant forms of a single RTK may play a causal role in very different types of cancer.  The Kit [[proto-oncogene]] encodes a tyrosine kinase receptor whose ligand is a paracrine protein called stem cell factor (SCF), which is important in [[hematopoiesis]] (formation of cells in blood).<ref name="Zsebo">{{cite journal |doi=10.1016/0092-8674(90)90302-U |title=Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor |year=1990 |last1=Zsebo |first1=Krisztina M. |last2=Williams |first2=David A. |last3=Geissler |first3=Edwin N. |last4=Broudy |first4=Virginia C. |last5=Martin |first5=Francis H. |last6=Atkins |first6=Harry L. |last7=Hsu |first7=Rou-Yin |last8=Birkett |first8=Neal C. |last9=Okino |first9=Kenneth H. |journal=Cell |volume=63 |pages=213–24 |pmid=1698556 |issue=1 |last10=Murdock |first10=Douglas C. |last11=Jacobsen |first11=Frederick W. |last12=Langley |first12=Keith E. |last13=Smith |first13=Kent A. |last14=Takeish |first14=Takashi |last15=Cattanach |first15=Bruce M. |last16=Galli |first16=Stephen J. |last17=Suggs |first17=Sidney V.|s2cid=39924379 }}</ref>  The Kit receptor and related tyrosine kinase receptors actually are inhibitory and effectively suppresses receptor firing.  Mutant forms of the Kit receptor, which fire constitutively in a ligand-independent fashion, are found in a diverse array of cancerous malignancies.<ref name="Rönnstrand">{{cite journal |doi=10.1007/s00018-004-4189-6 |title=Signal transduction via the stem cell factor receptor/c-Kit |year=2004 |last1=Rönnstrand |first1=L. |journal=Cellular and Molecular Life Sciences |volume=61 |issue=19–20 |pages=2535–48 |pmid=15526160|s2cid=2602233 |pmc=11924424 }}</ref>

====RTK pathway and cancer====
Research on [[thyroid cancer]] has elucidated the theory that paracrine signaling may aid in creating tumor microenvironments.  [[Chemokine]] transcription is upregulated when Ras is in the GTP-bound state.  The chemokines are then released from the cell, free to bind to another nearby cell.  Paracrine signaling between neighboring cells creates this positive feedback loop.  Thus, the constitutive transcription of upregulated proteins form ideal environments for tumors to arise.{{source needed|date=March 2025}}  Effectively, multiple bindings of ligands to the RTK receptors overstimulates the Ras-Raf-MAPK pathway, which [[Overexpression|overexpresses]] the [[mitogen]]ic and invasive capacity of cells.<ref name="Kolch ">{{cite journal |last1=Kolch |first1=Walter |pmid=11023813 |year=2000 |title=Meaningful relationships: The regulation of the Ras/Raf/MEK/ERK pathway by protein interactions |volume=351 |pages=289–305 |pmc=1221363 |journal=The Biochemical Journal |issue=2 |doi=10.1042/0264-6021:3510289}}</ref>

===JAK-STAT pathway===
In addition to RTK pathway, [[fibroblast growth factors]] can also activate the [[JAK-STAT signaling pathway]]. Instead of carrying covalently associated tyrosine kinase domains, Jak-STAT receptors form noncovalent complexes with tyrosine kinases of the Jak ([[Janus kinase]]) class. These receptors bind are for [[erythropoietin]] (important for [[erythropoiesis]]), [[thrombopoietin]] (important for [[platelet]] formation), and [[interferon]] (important for mediating immune cell function).<ref name="Aaronson">{{cite journal |bibcode=2002Sci...296.1653A |title=A Road Map for Those Who Don't Know JAK-STAT |last1=Aaronson |first1=David S. |last2=Horvath |first2=Curt M. |volume=296 |year=2002 |pages=1653–5 |journal=Science |doi=10.1126/science.1071545 |pmid=12040185 |issue=5573|s2cid=20857536 }}</ref>

After dimerization of the cytokine receptors following ligand binding, the JAKs transphosphorylate each other. The resulting phosphotyrosines attract STAT proteins. The STAT proteins dimerize and enter the nucleus to act as [[transcription factors]] to alter gene expression.<ref name="Aaronson"/> In particular, the STATs transcribe genes that aid in cell proliferation and survival – such as myc.<ref name="Rawlings">{{cite journal |doi=10.1242/jcs.00963 |title=The JAK/STAT signaling pathway |year=2004 |last1=Rawlings |first1=Jason S. |journal=Journal of Cell Science |volume=117 |issue=8 |pages=1281–3 |pmid=15020666 |last2=Rosler |first2=Kristin M. |last3=Harrison |first3=Douglas A.|doi-access=free }}</ref>

Phenotype and survival of mice after knockout of some JAK or STAT genes:<ref name="O’Shea">{{cite journal |doi=10.1016/S0092-8674(02)00701-8 |title=Cytokine signaling in 2002: new surprises in the Jak/Stat pathway |year=2002 |last1=O'Shea |first1=John J |last2=Gadina |first2=Massimo |last3=Schreiber |first3=Robert D |journal=Cell |volume=109 |issue=2 |pages=S121–31 |pmid=11983158|doi-access=free }}</ref> 
{| class="wikitable"
|-
! Knockout Gene !! Survival !! Phenotype
|-
| Jak1|| Lethal|| Neurologic Deficits
|-
| Jak2|| Lethal|| Failure in erythropoiesis
|-
| Stat1|| Viable|| Human dwarfism and [[craniosynostosis]] syndromes
|-
| Stat3|| Lethal|| Tissue specific phenotypes
|-
| Stat4|| Viable|| defective IL-12-driven Th1 differentiation, increased susceptibility to intracellular pathogens
|}

====Aberrant JAK-STAT pathway and bone mutations====
The JAK-STAT signaling pathway is instrumental in the development of limbs, specifically in its ability to regulate bone growth through paracrine signaling of cytokines. However, mutations in this pathway have been implicated in severe forms of dwarfism: [[thanatophoric dysplasia]] (lethal) and [[Achondroplasia|achondroplasic]] dwarfism (viable).<ref name="Bonaventure,">{{cite journal |doi=10.1002/(SICI)1096-8628(19960503)63:1<148::AID-AJMG26>3.0.CO;2-N |title=Common mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism |year=1996 |last1=Bonaventure |first1=J. |last2=Rousseau |first2=F. |last3=Legeai-Mallet |first3=L. |last4=Le Merrer |first4=M. |last5=Munnich |first5=A. |last6=Maroteaux |first6=P. |journal=American Journal of Medical Genetics |volume=63 |pages=148–54 |pmid=8723101 |issue=1}}</ref> This is due to a mutation in a [[Fibroblast growth factor|Fgf]] gene, causing a premature and constitutive activation of the [[Stat1]] transcription factor. [[Chondrocyte]] cell division is prematurely terminated, resulting in lethal dwarfism. Rib and limb bone growth plate cells are not transcribed. Thus, the inability of the rib cage to expand prevents the newborn's breathing.<ref name="Shiang,">{{cite journal |doi=10.1016/0092-8674(94)90302-6 |title=Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia |year=1994 |last1=Shiang |first1=Rita |last2=Thompson |first2=Leslie M. |last3=Zhu |first3=Ya-Zhen |last4=Church |first4=Deanna M. |last5=Fielder |first5=Thomas J. |last6=Bocian |first6=Maureen |last7=Winokur |first7=Sara T. |last8=Wasmuth |first8=John J. |journal=Cell |volume=78 |issue=2 |pages=335–42 |pmid=7913883|s2cid=20325070 }}</ref>

====JAK-STAT pathway and cancer====
Research on paracrine signaling through the JAK-STAT pathway revealed its potential in activating invasive behavior of ovarian [[epithelium|epithelial cells]]. This epithelial to [[mesenchymal]] transition is highly evident in [[metastasis]].<ref name="Kalluri">{{cite journal |doi=10.1172/JCI39104 |title=The basics of epithelial-mesenchymal transition |year=2009 |last1=Kalluri |first1=Raghu |last2=Weinberg |first2=Robert A. |journal=Journal of Clinical Investigation |volume=119 |issue=6 |pages=1420–8 |pmid=19487818 |pmc=2689101}}</ref> Paracrine signaling through the JAK-STAT pathway is necessary in the transition from stationary epithelial cells to mobile mesenchymal cells, which are capable of invading surrounding tissue. Only the JAK-STAT pathway has been found to induce migratory cells.<ref name="Silver">{{cite journal|last1=Silver|first1=Debra L.|last2=Montell|first2=Denise J.|author-link2=Denise Montell|year=2001|title=Paracrine Signaling through the JAK/STAT Pathway Activates Invasive Behavior of Ovarian Epithelial Cells in Drosophila|journal=Cell|volume=107|issue=7|pages=831–41|doi=10.1016/S0092-8674(01)00607-9|pmid=11779460|doi-access=free}}</ref>

== Hedgehog family ==
The [[Hedgehog signaling pathway|Hedgehog protein family]] is involved in induction of cell types and the creation of tissue boundaries and patterning and are found in all bilateral organisms. Hedgehog proteins were first discovered and studied in ''[[Drosophila]]''.  Hedgehog proteins produce key signals for the establishment of limb and [[body plan]] of fruit flies as well as [[homeostasis]] of adult tissues, involved in late [[embryogenesis]] and [[metamorphosis]]. At least three "Drosophila" hedgehog [[homologs]] have been found in vertebrates: sonic hedgehog, desert hedgehog, and Indian hedgehog. Sonic hedgehog ([[Sonic hedgehog|SHH]]) has various roles in vertebrae development, mediating signaling and regulating the organization of central nervous system, limb, and [[somite]] [[Polarity in embryogenesis|polarity]]. Desert hedgehog ([[DHH (hedgehog)|DHH]]) is expressed in the [[Sertoli cell]]s involved in [[spermatogenesis]]. Indian hedgehog ([[IHH (protein)|IHH]]) is expressed in the gut and cartilage, important in postnatal bone growth.<ref>{{cite journal |doi=10.1101/gad.938601 |title=Hedgehog signaling in animal development: Paradigms and principles |year=2001 |last1=Ingham |first1=P. W. |journal=Genes & Development |volume=15 |issue=23 |pages=3059–87 |pmid=11731473 |last2=McMahon |first2=AP|doi-access=free }}</ref><ref>{{cite journal |doi=10.1006/dbio.1995.0010 |title=''Hedgehog'' and ''Bmp'' Genes Are Coexpressed at Many Diverse Sites of Cell–Cell Interaction in the Mouse Embryo |year=1995 |last1=Bitgood |first1=Mark J. |last2=McMahon |first2=Andrew P. |journal=Developmental Biology |volume=172 |pages=126–38 |pmid=7589793 |issue=1|doi-access=free }}</ref><ref name="Hedgehog Signaling Pathway">{{cite journal |doi=10.1126/stke.4072007cm6 |title=Hedgehog Signaling Pathway |year=2007 |last1=Jacob |first1=L. |last2=Lum |first2=L. |journal=Science's STKE |volume=2007 |issue=407 |pages=cm6 |pmid=17925577|s2cid=35653781 }}</ref>

=== Hedgehog signaling pathway ===
[[File:HedgehogCiR.svg|thumb|left| Production of the CiR transcriptional repressor when Hh is not bound to Patched. In the diagram, "P" represents  [[phosphate]].]]
[[File:HedgehogActive.svg|thumb|right| When Hh is bound to Patched (PTCH), Ci protein is able to act as a transcription factor in the nucleus.]]

Members of the Hedgehog protein family act by binding to a [[transmembrane]] "[[Patched]]" receptor, which is bound to the "[[Smoothened]]" protein, by which the Hedgehog signal can be [[Signal transduction|transduced]]. In the absence of Hedgehog, the Patched receptor inhibits Smoothened action. Inhibition of Smoothened causes the [[ci protein|Cubitus interruptus]] (Ci), Fused, and Cos protein complex attached to microtubules to remain intact. In this conformation, the Ci protein is cleaved so that a portion of the protein is allowed to enter the nucleus and act as a transcriptional [[repressor]]. In the presence of Hedgehog, Patched no longer inhibits Smoothened. Then active Smoothened protein is able to inhibit [[Protein kinase A|PKA]] and Slimb, so that the Ci protein is not cleaved. This intact Ci protein can enter the nucleus, associate with CPB protein and act as a transcriptional [[activator (genetics)|activator]], inducing the expression of Hedgehog-response genes.<ref name="Hedgehog Signaling Pathway"/><ref>{{cite journal |doi=10.1016/S0959-437X(98)80117-2 |title=New players and puzzles in the Hedgehog signaling pathway |year=1998 |last1=Johnson |first1=Ronald L |last2=Scott |first2=Matthew P |journal=Current Opinion in Genetics & Development |volume=8 |issue=4 |pages=450–6 |pmid=9729722|doi-access=free }}</ref><ref>{{cite journal |doi=10.1016/S0959-437X(02)00333-7 |title=Hedgehog signal transduction: Recent findings |year=2002 |last1=Nybakken |first1=K |journal=Current Opinion in Genetics & Development |volume=12 |issue=5 |pages=503–11 |pmid=12200154 |last2=Perrimon |first2=N}}</ref>

=== Hedgehog signaling pathway and cancer ===
The Hedgehog Signaling pathway is critical in proper tissue patterning and orientation during normal development of most animals. Hedgehog proteins induce [[cell proliferation]] in certain cells and differentiations in others. Aberrant activation of the Hedgehog pathway has been implicated in several types of [[cancers]], [[Basal Cell Carcinoma]] in particular. This uncontrolled activation of the Hedgehog proteins can be caused by mutations to the signal pathway, which would be [[ligand]] independent, or a mutation that causes [[overexpression]] of the Hedgehog protein, which would be ligand dependent. In addition, therapy-induced Hedgehog pathway activation has been shown to be necessary for progression of Prostate Cancer tumors after [[androgen deprivation therapy]].<ref>{{cite journal| vauthors=Lubik AA, Nouri M, Truong S, Ghaffari M, Adomat HH, Corey E, Cox ME, Li N, Guns ES, Yenki P, Pham S, Buttyan R | title=Paracrine Sonic Hedgehog Signaling Contributes Significantly to Acquired Steroidogenesis in the Prostate Tumor Microenvironment|journal=International Journal of Cancer| volume=140| issue=2| pages=358–369|date=2016|pmid=27672740|doi=10.1002/ijc.30450| s2cid=2354209| doi-access=free}}</ref> This connection between the Hedgehog signaling pathway and human cancers may provide for the possible of therapeutic intervention as treatment for such cancers. The Hedgehog signaling pathway is also involved in normal regulation of [[stem-cell]] populations, and required for normal growth and regeneration of damaged organs. This may provide another possible route for [[tumorigenesis]] via the Hedgehog pathway.<ref>{{cite journal |doi=10.1534/genetics.104.039420 |title=A Genetic Screen in Drosophila for Identifying Novel Components of the Hedgehog Signaling Pathway |year=2005 |last1=Collins |first1=R. T. |journal=Genetics |volume=170 |pages=173–84 |pmid=15744048 |last2=Cohen |first2=SM |issue=1 |pmc=1449730}}</ref><ref>{{cite journal |doi=10.1158/1078-0432.CCR-06-1736 |title=The Hedgehog Signaling Pathway in Cancer |year=2006 |last1=Evangelista |first1=M. |last2=Tian |first2=H. |last3=De Sauvage |first3=F. J. |journal=Clinical Cancer Research |volume=12 |issue=20 |pages=5924–8 |pmid=17062662|doi-access=free }}</ref><ref>{{cite journal |doi=10.1038/35077219 |year=2001 |last1=Taipale |first1=Jussi |last2=Beachy |first2=Philip A. |journal=Nature |volume=411 |issue=6835 |pages=349–54 |pmid=11357142 |title=The Hedgehog and Wnt signaling pathways in cancer|bibcode=2001Natur.411..349T |s2cid=4414768 }}</ref>

== Wnt family ==
[[File:Wnt signaling in biological signal transduction.svg|thumbnail|Figure of the three main pathways of Wnt signaling in biological signal transduction.]]

The [[Wnt protein]] family includes a large number of [[cysteine]]-rich [[glycoproteins]]. The Wnt proteins activate [[signal transduction]] cascades via three different pathways, the canonical [[Wnt pathway]], the noncanonical [[Planar cell polarity|planar cell polarity (PCP) pathway]], and the noncanonical Wnt/Ca<sup>2+</sup> pathway. Wnt proteins appear to control a wide range of developmental processes and have been seen as necessary for control of [[Spindle apparatus|spindle]] orientation, cell polarity, cadherin mediated adhesion, and early development of embryos in many different organisms. Current research has indicated that deregulation of Wnt signaling plays a role in tumor formation, because at a cellular level, Wnt proteins often regulated [[cell proliferation]], cell morphology, cell [[motility]], and cell fate.<ref>{{cite journal |doi=10.1101/gad.11.24.3286 |title=Wnt signaling: A common theme in animal development |year=1997 |last1=Cadigan |first1=K. M. |last2=Nusse |first2=R. |journal=Genes & Development |volume=11 |issue=24 |pages=3286–305 |pmid=9407023|doi-access=free }}</ref>

=== The canonical Wnt signaling pathway ===
[[File:Canonical Wnt pathway without Wnt..jpg|thumb|Canonical Wnt pathway without Wnt.|right]]

In the [[WNT pathway|canonical pathway]], Wnt proteins binds to its transmembrane receptor of the [[Frizzled]] family of proteins. The binding of Wnt to a Frizzled protein activates the [[Dishevelled]] protein. In its active state the Dishevelled protein inhibits the activity of the glycogen synthase kinase 3 ([[GSK3]]) enzyme. Normally active GSK3 prevents the dissociation of β-catenin to the [[Adenomatous polyposis coli|APC]] protein, which results in [[β-catenin]] degradation. Thus inhibited GSK3, allows β-catenin to dissociate from APC, accumulate, and travel to nucleus. In the nucleus β-catenin associates with Lef/Tcf [[transcription factor]], which is already working on DNA as a repressor, inhibiting the transcription of the genes it binds. Binding of β-catenin to Lef/Tcf works as a transcription activator, activating the transcription of the Wnt-responsive genes.<ref name="ncbi.nlm.nih.gov">{{cite journal |last1=Dale |first1=Trevor C. |pmid=9425102 |year=1998 |title=Signal transduction by the Wnt family of ligands |volume=329 |pages=209–23 |pmc=1219034 |journal=The Biochemical Journal |issue=Pt 2 |doi=10.1042/bj3290209}}</ref><ref name="Chen, X. P.M">{{cite journal |doi=10.1111/j.1745-7270.2008.00440.x |title=Wnt signaling: The good and the bad |year=2008 |last1=Chen |first1=Xi |last2=Yang |first2=Jun |last3=Evans |first3=Paul M |last4=Liu |first4=Chunming |journal=Acta Biochimica et Biophysica Sinica |volume=40 |issue=7 |pages=577–94 |pmid=18604449 |pmc=2532600}}</ref><ref name="Wnt signal transduction pathways.">{{cite journal |doi=10.4161/org.4.2.5851 |title=Wnt signal transduction pathways |year=2008 |last1=Komiya |first1=Yuko |last2=Habas |first2=Raymond |journal=Organogenesis |volume=4 |issue=2 |pages=68–75 |pmid=19279717 |pmc=2634250}}</ref>

=== The noncanonical Wnt signaling pathways ===
The noncanonical Wnt pathways provide a signal transduction pathway for Wnt that does not involve [[β-catenin]]. In the noncanonical pathways, Wnt affects the [[actin]] and [[Microtubule|microtubular]] [[cytoskeleton]] as well as [[gene transcription]].

==== The noncanonical planar cell polarity (PCP) pathway ====
[[File:Noncanonical Wnt PCP Pathway.jpg|thumb|Noncanonical Wnt Planar Cell Polarity pathway.|left]]

The noncanonical PCP pathway regulates cell [[morphology (biology)|morphology]], [[Cell division|division]], and [[Cell (biology)#Movement or motility|movement]]. Once again Wnt proteins binds to and activates Frizzled so that Frizzled activates a Dishevelled protein that is tethered to the plasma membrane through a [[Prickle (protein)|Prickle protein]] and transmembrane Stbm protein. The active Dishevelled activates RhoA [[GTPase]] through Dishevelled associated activator of [[Morphogenesis|morphogenesis 1]] (Daam1) and the [[Rac protein]]. Active RhoA is able to induce cytoskeleton changes by activating Roh-associated kinase (ROCK) and affect gene transcription directly. Active Rac can directly induce cytoskeleton changes and affect gene transcription through activation of JNK.<ref name="ncbi.nlm.nih.gov"/><ref name="Chen, X. P.M"/><ref name="Wnt signal transduction pathways."/>

==== The noncanonical Wnt/Ca<sup>2+</sup> pathway====
[[File:Noncanonical Wnt calcium pathway.jpg|thumb|Noncanonical Wnt/calcium pathway.|right]]

The noncanonical Wnt/Ca<sup>2+</sup> pathway regulates intracellular [[calcium]] levels. Again Wnt binds and activates to Frizzled. In this case however activated Frizzled causes a coupled G-protein to activate a [[phospholipase]] (PLC), which interacts with and splits PIP<sub>2</sub> into DAG and IP<sub>3</sub>. IP<sub>3</sub> can then bind to a receptor on the [[endoplasmic reticulum]] to release intracellular calcium stores, to induce calcium-dependent gene expression.<ref name="ncbi.nlm.nih.gov"/><ref name="Chen, X. P.M"/><ref name="Wnt signal transduction pathways."/>

=== Wnt signaling pathways and cancer ===
The Wnt signaling pathways are critical in cell-cell signaling during normal development and embryogenesis and required for maintenance of adult tissue, therefore it is not difficult to understand why disruption in Wnt signaling pathways can promote human [[degenerative disease]] and [[cancer]].

The Wnt signaling pathways are complex, involving many different elements, and therefore have many targets for misregulation. Mutations that cause constitutive activation of the Wnt signaling pathway lead to tumor formation and cancer. Aberrant activation of the Wnt pathway can lead to increase cell proliferation. Current research is focused on the action of the Wnt signaling pathway the regulation of stem cell choice to proliferate and self renew. This action of Wnt signaling in the possible control and maintenance of stem cells, may provide a possible treatment in cancers exhibiting aberrant Wnt signaling.<ref>{{cite journal |doi=10.1146/annurev.cellbio.20.010403.113126 |title=The Wnt Signaling Pathway in Development and Disease |year=2004 |last1=Logan |first1=Catriona Y. |last2=Nusse |first2=Roel |journal=Annual Review of Cell and Developmental Biology |volume=20 |pages=781–810 |pmid=15473860|citeseerx=10.1.1.322.311 }}</ref><ref>{{cite journal |pmid=12707770 |year=2003 |last1=Lustig |first1=B |last2=Behrens |first2=J |title=The Wnt signaling pathway and its role in tumor development |volume=129 |issue=4 |pages=199–221 |doi=10.1007/s00432-003-0431-0 |journal=Journal of Cancer Research and Clinical Oncology|s2cid=28959851 }}</ref><ref>{{cite journal |doi=10.1007/s12015-007-0001-y |title=The Wnt Signal Transduction Pathway in Stem Cells and Cancer Cells: Influence on Cellular Invasion |year=2007 |last1=Neth |first1=Peter |last2=Ries |first2=Christian |last3=Karow |first3=Marisa |last4=Egea |first4=Virginia |last5=Ilmer |first5=Matthias |last6=Jochum |first6=Marianne |journal=Stem Cell Reviews |volume=3 |pages=18–29 |pmid=17873378 |issue=1|s2cid=25793825 }}</ref>

== TGF-β superfamily ==
"[[Transforming growth factor|TGF]]" (Transforming Growth Factor) is a family of proteins that includes 33 members that encode [[protein dimer|dimeric]], secreted polypeptides that regulate development.<ref name="DoijournalpgenMissing">{{cite journal |doi=10.1371/journal.pgen.0020216 |title=Genetic Analysis of the Roles of BMP2, BMP4, and BMP7 in Limb Patterning and Skeletogenesis |year=2006 |last1=Bandyopadhyay |first1=Amitabha |last2=Tsuji |first2=Kunikazu |last3=Cox |first3=Karen |last4=Harfe |first4=Brian D. |last5=Rosen |first5=Vicki |last6=Tabin |first6=Clifford J. |journal=PLOS Genetics |volume=2 |issue=12 |pages=e216 |pmid=17194222 |pmc=1713256 |doi-access=free }}</ref> Many developmental processes are under its control including gastrulation, axis symmetry of the body, organ morphogenesis, and tissue homeostasis in adults.<ref>{{cite journal |doi=10.1126/science.1071809 |title=Signal Transduction by the TGF-β Superfamily |year=2002 |last1=Attisano |first1=Liliana |journal=Science |volume=296 |issue=5573 |pages=1646–7 |pmid=12040180 |last2=Wrana |first2=Jeffrey L.|bibcode = 2002Sci...296.1646A |s2cid=84138159 }}</ref> All [[TGF-β]] ligands bind to either Type I or Type II receptors, to create heterotetramic complexes.<ref name="Wrana, J. L. 2008 pp. 179-202">{{cite book |first1=Jeffrey L. |last1=Wrana |first2=Barish |last2=Ozdamar |first3=Christine |last3=Le Roy |first4=Hassina |last4=Benchabane |chapter=Signaling Receptors of the TGF-β Family |chapter-url=http://cshmonographs.org/index.php/monographs/article/view/3838 |pages=151–77 |editor1-first=Rik |editor1-last=Derynck |editor2-first=Kohei |editor2-last=Miyazono |title=The TGF-β Family |year=2008 |publisher=CSHL Press |isbn=978-0-87969-752-5}}</ref>

=== TGF-β pathway ===
The [[TGF beta signaling pathway|TGF-β pathway]] regulates many cellular processes in developing embryo and adult organisms, including [[cell growth]], [[Cellular differentiation|differentiation]], [[apoptosis]], and [[homeostasis]]. There are five kinds of type II receptors and seven types of type I receptors in humans and other mammals. These receptors are known as "dual-specificity kinases" because their cytoplasmic kinase domain has weak tyrosine kinase activity but strong [[serine]]/[[threonine]] kinase activity.<ref>{{cite book |last1=ten Dijke |first1=Peter |last2=Heldin |first2=Carl-Henrik |year=2006 |chapter=The Smad family |chapter-url=https://books.google.com/books?id=ZavnLLA_6kgC&pg=PA1 |title=Smad Signal Transduction: Smads in Proliferation, Differentiation and Disease |volume=5 |series=Proteins and Cell Regulation |editor1-first=Peter |editor1-last=ten Dijke |editor2-first=Carl-Henrik |editor2-last=Heldin |pages=1–13 |location=Dordrecht |publisher=Springer |isbn=978-1-4020-4709-1}}</ref> When a TGF-β superfamily ligand binds to the type II receptor, it recruits a type I receptor and activates it by phosphorylating the serine or threonine residues of its "GS" box.<ref>{{cite journal |first1=Aristidis |last1=Moustakas |pmid=12154066 |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=12154066 |title=Smad signaling network |date=2002-09-01 |journal=Journal of Cell Science |volume=115 |issue=17 |pages=3355–6|doi=10.1242/jcs.115.17.3355 |doi-access=free }}</ref> This forms an activation complex that can then phosphorylate SMAD proteins.

[[File:SMAD apoptosis.svg|framed|right|SMAD Signaling Pathway Activated by TGF-β]]

=== SMAD pathway ===
There are three classes of SMADs:
# Receptor-regulated SMAD ([[R-SMAD]])
# Common-mediator SMAD (Co-SMAD)
# Inhibitory SMAD ([[I-SMAD]])

Examples of SMADs in each class:<ref name="pmid11779503">{{cite journal |doi=10.1016/S1097-2765(01)00421-X |title=Crystal Structure of a Phosphorylated Smad2 |year=2001 |last1=Wu |first1=Jia-Wei |last2=Hu |first2=Min |last3=Chai |first3=Jijie |last4=Seoane |first4=Joan |last5=Huse |first5=Morgan |last6=Li |first6=Carey |last7=Rigotti |first7=Daniel J. |last8=Kyin |first8=Saw |last9=Muir |first9=Tom W. |journal=Molecular Cell |volume=8 |issue=6 |pages=1277–89 |pmid=11779503 |last10=Fairman |first10=Robert |last11=Massagué |first11=Joan |last12=Shi |first12=Yigong|doi-access=free }}</ref><ref name="pmid9214508">{{cite journal |doi=10.1038/40431 |year=1997 |last1=Pavletich |first1=Nikola P. |last2=Hata |first2=Yigong |last3=Lo |first3=Akiko |last4=Massagué |first4=Roger S. |last5=Pavletich |first5=Joan |journal=Nature |volume=388 |issue=6637 |pages=87–93 |pmid=9214508 |title=A structural basis for mutational inactivation of the tumour suppressor Smad4|bibcode=1997Natur.388R..87S |doi-access=free }}</ref><ref name="pmid11483516">{{cite journal |doi=10.1093/emboj/20.15.4132 |title=Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads |year=2001 |last1=Itoh |first1=Fumiko |journal=The EMBO Journal |volume=20 |issue=15 |pages=4132–42 |pmid=11483516 |last2=Asao |first2=Hironobu |last3=Sugamura |first3=Kazuo |last4=Heldin |first4=Carl-Henrik |last5=Ten Dijke |first5=Peter |last6=Itoh |first6=Susumu |pmc=149146}}</ref>
{| class="wikitable"
|-
! Class !! SMADs
|-
| [[R-SMAD]]|| [[mothers against decapentaplegic homolog 1|SMAD1]], [[mothers against decapentaplegic homolog 2|SMAD2]], [[mothers against decapentaplegic homolog 3|SMAD3]], [[mothers against decapentaplegic homolog 5|SMAD5]] and [[mothers against decapentaplegic homolog 9|SMAD8/9]]
|-
| Co-SMAD || [[mothers against decapentaplegic homolog 4|SMAD4]]
|-
| [[I-SMAD]]|| [[mothers against decapentaplegic homolog 6|SMAD6]] and [[mothers against decapentaplegic homolog 7|SMAD7]]
|}

The TGF-β superfamily activates members of the [[SMAD (protein)|SMAD]] family, which function as transcription factors. Specifically, the type I receptor, activated by the type II receptor, phosphorylates [[R-SMAD]]s that then bind to the co-SMAD, [[mothers against decapentaplegic homolog 4|SMAD4]]. The R-SMAD/Co-SMAD forms a complex with [[importin]] and enters the nucleus, where they act as [[transcription factor]]s and either up-regulate or down-regulate in the expression of a target gene.

Specific TGF-β ligands will result in the activation of either the SMAD2/3 or the SMAD1/5 [[R-SMAD]]s. For instance, when [[activin]], [[NODAL|Nodal]], or [[Transforming growth factor beta|TGF-β ligand]] binds to the receptors, the [[phosphorylated]] receptor complex can activate [[mothers against decapentaplegic homolog 2|SMAD2]] and [[mothers against decapentaplegic homolog 3|SMAD3]] through phosphorylation. However, when a BMP ligand binds to the receptors, the phosphorylated receptor complex activates [[mothers against decapentaplegic homolog 1|SMAD1]] and [[mothers against decapentaplegic homolog 5|SMAD5]]. Then, the Smad2/3 or the Smad1/5 complexes form a dimer complex with [[mothers against decapentaplegic homolog 4|SMAD4]] and become [[transcription factors]]. Though there are many [[R-SMAD]]s involved in the pathway, there is only one co-SMAD, [[mothers against decapentaplegic homolog 4|SMAD4]].<ref>{{cite journal |doi=10.1038/nrm2297 |title=TGFβ–SMAD signal transduction: Molecular specificity and functional flexibility |year=2007 |last1=Schmierer |first1=Bernhard |last2=Hill |first2=Caroline S. |journal=Nature Reviews Molecular Cell Biology |volume=8 |issue=12 |pages=970–82 |pmid=18000526|s2cid=131895 }}</ref>

=== Non-SMAD pathway ===
Non-Smad signaling proteins contribute to the responses of the TGF-β pathway in three ways. First, non-Smad signaling pathways phosphorylate the Smads. Second, Smads directly signal to other pathways by communicating directly with other signaling proteins, such as kinases. Finally, the TGF-β receptors directly phosphorylate non-Smad proteins.<ref>{{cite journal |doi=10.1242/jcs.02554 |title=Non-Smad TGF-β signals |year=2005 |last1=Moustakas |first1=Aristidis |last2=Heldin |first2=Carl-Henrik |journal=Journal of Cell Science |volume=118 |issue=16 |pages=3573–84 |pmid=16105881|doi-access=free }}</ref>

=== Members of TGF-β superfamily ===

====1. TGF-β family ====
This family includes [[TGFβ1|TGF-β1]], [[TGFβ2|TGF-β2]], [[TGFβ3|TGF-β3]], and TGF-β5. They are involved in positively and negatively regulation of [[cell division]], the formation of the [[extracellular matrix]] between cells, [[apoptosis]], and [[embryogenesis]]. They bind to [[TGF-beta receptor type-2|TGF-β type II receptor]] (TGFBRII).

TGF-β1 stimulates the synthesis of [[collagen]] and [[fibronectin]] and inhibits the degradation of the [[extracellular matrix]]. Ultimately, it increases the production of extracellular matrix by [[epithelial cells]].<ref name="Wrana, J. L. 2008 pp. 179-202"/>
TGF-β proteins regulate epithelia by controlling where and when they branch to form kidney, lung, and salivary gland ducts.<ref name="Wrana, J. L. 2008 pp. 179-202"/>

==== 2. Bone morphogenetic protein (BMPs) family ====
Members of the BMP family were originally found to induce [[bone formation]], as their name suggests. However, BMPs are very multifunctional and can also regulate [[apoptosis]], [[cell migration]], [[cell division]], and [[Cellular differentiation|differentiation]]. They also specify the anterior/posterior axis, induce growth, and regulate [[homeostasis]].<ref name="DoijournalpgenMissing" />

The BMPs bind to the [[BMPR2|bone morphogenetic protein receptor type II]] (BMPR2). Some of the proteins of the [[Bone morphogenetic protein|BMP]] family are [[BMP4]] and [[BMP7]]. [[BMP4]] promotes bone formation, causes cell death, or signals the formation of [[epidermis (skin)|epidermis]], depending on the tissue it is acting on. [[BMP7]] is crucial for kidney development, sperm synthesis, and neural tube polarization. Both [[BMP4]] and [[BMP7]] regulate mature ligand stability and processing, including degrading ligands in lysosomes.<ref name="DoijournalpgenMissing" /> BMPs act by diffusing from the cells that create them.<ref>{{cite journal |doi=10.1016/S0960-9822(01)00684-4 |title=Action Range of BMP is Defined by Its N-Terminal Basic Amino Acid Core |year=2002 |last1=Ohkawara |first1=Bisei |last2=Iemura |first2=Shun-Ichiro |last3=Ten Dijke |first3=Peter |last4=Ueno |first4=Naoto |journal=Current Biology |volume=12 |issue=3 |pages=205–9 |pmid=11839272|doi-access=free }}</ref>

==== Other members of TGF-β superfamily====
* [[VG-1 (cell line)|Vg1 Family]]
* [[Activin and inhibin|Activin Family]]
** Involved in [[embryogenesis]] and [[osteogenesis]]
** Regulate [[insulin]] and [[pituitary]], gonadal, and [[hypothalamic]] hormones
** Nerve cell survival factors 
**3 Activins: [[Activin and inhibin|Activin A]], [[Activin and inhibin|Activin B]] and [[Activin and inhibin|Activin AB]].
* [[Glial cell line-derived neurotrophic factor|Glial-Derived Neurotrophic Factor (GDNF)]]
** Needed for kidney and [[enteric neuron]] [[Cell differentiation|differentiation]]
* [[Anti-Müllerian hormone|Müllerian Inhibitory Factor]]
** Involved in mammalian sex determination
* [[Nodal (protein)|Nodal]] 
** Binds to [[ACVR2B|Activin A Type 2B receptor]]
** Forms receptor complex with [[ACVR1B|Activin A Type 1B receptor]] or with [[ACVR1C|Activin A Type 1C receptor]].<ref>{{cite journal |doi=10.1074/jbc.M400641200 |title=Nodal and ALK7 Inhibit Proliferation and Induce Apoptosis in Human Trophoblast Cells |year=2004 |last1=Munir |first1=Sadia |journal=Journal of Biological Chemistry |volume=279 |issue=30 |pages=31277–86 |pmid=15150278 |last2=Xu |first2=Guoxiong |last3=Wu |first3=Yaojiong |last4=Yang |first4=Burton |last5=Lala |first5=Peeyush K. |last6=Peng |first6=Chun|doi-access=free }}</ref>
*[[Growth and differentiation factor|Growth and differentiation factors (GDFs)]]

===Summary table of TGF-β signaling pathway===
{| class="wikitable"
!style="background:Gray; color:white"|TGF Beta superfamily ligand !!style="background:#FFC0CB; color:Black"| [[TGF beta receptor 2|Type II Receptor]] !!style="background:#F7931D;  color:white" |[[TGF beta receptor 1|Type I Receptor]] !!style="background:#DDA0DD;  color:white" | [[R-SMAD]]s !!style="background:Yellow;  color:black" | Co-SMAD !!style="background:Turquoise; color:Black"|Ligand Inhibitors
|-
! [[Activin and inhibin|Activin A]]
|[[ACVR2A]]
|[[ACVR1B]] (ALK4)
|[[SMAD2]], [[SMAD3]]
|[[SMAD4]]
|[[Follistatin]]
|-
! [[GDF1]]
|[[ACVR2A]]
|[[ACVR1B]] (ALK4)
|[[SMAD2]], [[SMAD3]]
|[[SMAD4]]
|
|-
! [[GDF11]]
|[[ACVR2B]]
|[[ACVR1B]] (ALK4), [[TGFβRI]] (ALK5)
|[[SMAD2]], [[SMAD3]]
|[[SMAD4]]
|
|-
![[Bone morphogenetic proteins]]
|[[BMPR2]]
|[[BMPR1A]] (ALK3), [[BMPR1B]] (ALK6)
|[[SMAD1]] [[SMAD5]], [[SMAD8]]
|[[SMAD4]]
|[[Noggin (protein)|Noggin]], [[Chordin]], [[DAN (protein)|DAN]]
|-
![[Nodal (protein)|Nodal]]
|[[ACVR2B]]
|[[ACVR1B]] (ALK4), [[ACVR1C]] (ALK7)
||[[SMAD2]], [[SMAD3]]
|[[SMAD4]]
|[[Lefty (protein)|Lefty]]
|-
![[Transforming growth factor beta|TGFβs]]
|[[TGFβRII]]
|[[TGFβRI]] (ALK5)
||[[SMAD2]], [[SMAD3]]
|[[SMAD4]]
|[[LTBP1]], [[THBS1]], [[Decorin]]
|}

==Examples==
[[Growth factor]] and [[clotting factor]]s are paracrine signaling agents. The local action of growth factor signaling plays an especially important role in the development of tissues. Also, [[retinoic acid]], the active form of [[vitamin A]], functions in a paracrine fashion to regulate gene expression during embryonic development in higher animals.<ref name="Duester">{{cite journal |last1=Duester |first1=Gregg |title=Retinoic acid synthesis and signaling during early organogenesis |journal=Cell |volume=134 |issue=6 |pages=921–31 |date=September 2008 |pmid=18805086 |pmc=2632951 |doi=10.1016/j.cell.2008.09.002}}</ref> 
In insects, [[Allatostatin]] controls growth through paracrine action on the corpora allata.{{citation needed|date=February 2013}}


In mature organisms, paracrine signaling is involved in responses to [[allergen]]s, tissue repair, the formation of [[scar|scar tissue]], and blood [[clotting]].{{Citation needed|date=September 2009}} [[Histamine]] is a paracrine that is released by immune cells in the bronchial tree. Histamine causes the smooth muscle cells of the bronchi to constrict, narrowing the airways.<ref name="Openstax Anatomy & Physiology attribution">{{CC-notice|cc=by4|url=https://openstax.org/books/anatomy-and-physiology/pages/17-1-an-overview-of-the-endocrine-system}} {{cite book|last1=Betts|first1=J Gordon|last2=Desaix|first2=Peter|last3=Johnson|first3=Eddie|last4=Johnson|first4=Jody E|last5=Korol|first5=Oksana|last6=Kruse|first6=Dean|last7=Poe|first7=Brandon|last8=Wise|first8=James|last9=Womble|first9=Mark D|last10=Young|first10=Kelly A|title=Anatomy & Physiology|location=Houston|publisher=OpenStax CNX|isbn=978-1-947172-04-3|date=July 24, 2023|at=17.1 Overview of the endocrine system}}</ref>

==See also==
*[[cAMP dependent pathway]]
*[[Crosstalk (biology)]]
*[[Lipid signaling]]
*[[Local hormone]] – either a paracrine hormone, or a hormone acting in both a paracrine and an endocrine fashion
*[[MAPK/ERK pathway|MAPK signaling pathway]]
*[[Netpath]] – A curated resource of signal transduction pathways in humans
*[[Paracrine regulator]]

==References==
{{Reflist|30em}}

==External links==
* {{MeshName|Paracrine+Signaling}}
* {{DorlandsDict|six/000078100|paracrine}}

{{Cell signaling}}

[[Category:Signal transduction]]