Incellular biology,paracrine signaling is a form ofcell signaling, a type ofcellular communication in which acell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known asparacrine factorsdiffuse over a relatively short distance (local action), as opposed to cell signaling byendocrine factors,hormones which travel considerably longer distances via thecirculatory system;juxtacrine interactions; andautocrine signaling. Cells that produce paracrine factors secrete them into the immediateextracellular 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.

Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set ofreceptors and pathways. In fact, differentorgans in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development.^[1] The highly conserved receptors and pathways can be organized into four major families based on similar structures:fibroblast growth factor (FGF) family,Hedgehog family,Wnt family, andTGF-β superfamily. Binding of a paracrine factor to its respective receptor initiatessignal transduction cascades, eliciting different responses.

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 beingcompetent. Additionally, the responding cell must also have the ability to be mechanistically induced.

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.^[2][3] To fulfill many diverse functions, FGFs can be alternatively spliced or even have different initiation codons to create hundreds of different FGFisoforms.^[4]

One of the most important functions of the FGF receptors (FGFR) is in limb development. This signaling involves nine differentalternatively splicedisoforms of the receptor.^[5]Fgf8 andFgf10 are two of the critical players in limb development. In the forelimb initiation and limb growth in mice, axial (lengthwise) cues from the intermediatemesoderm producesTbx5, which subsequently signals to the samemesoderm to produceFgf10.Fgf10 then signals to theectoderm to begin production ofFgf8, which also stimulates the production ofFgf10. Deletion ofFgf10 results in limbless mice.^[6]

Additionally, paracrine signaling of Fgf is essential in the developing eye of chicks. Thefgf8mRNA becomes localized in what differentiates into the neuralretina of theoptic cup. These cells are in contact with the outer ectoderm cells, which will eventually become the lens.^[4]

Phenotype and survival of mice after knockout of some FGFR genes:^[5]

Paracrine signaling throughfibroblast growth factors and its respective receptors utilizes the receptortyrosine pathway. This signaling pathway has been highly studied, usingDrosophila eyes and human cancers.^[7]

Binding of FGF to FGFRphosphorylates the idlekinase and activates the RTK pathway. This pathway begins at the cell membrane surface, where aligand binds to its specific receptor. Ligands that bind to RTKs includefibroblast growth factors, epidermal growth factors, platelet-derived growth factors, andstem cell factor.^[7] This dimerizes the transmembrane receptor to another RTK receptor, which causes the autophosphorylation and subsequentconformational change of thehomodimerized 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 thelipid bilayer, and into thecytoplasm, the binding of the receptor to the ligand also causes the trans phosphorylation of the cytoplasmic domain of the receptor.^[8]

Anadaptor 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 ofRas 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.^[9]

Paracrine signaling of growth factors between nearby cells has been shown to exacerbatecarcinogenesis. In fact, mutant forms of a single RTK may play a causal role in very different types of cancer. The Kitproto-oncogene encodes a tyrosine kinase receptor whose ligand is a paracrine protein called stem cell factor (SCF), which is important inhematopoiesis (formation of cells in blood).^[10] 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.^[11]

Research onthyroid 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.^{[citation needed]} Effectively, multiple bindings of ligands to the RTK receptors overstimulates the Ras-Raf-MAPK pathway, whichoverexpresses themitogenic and invasive capacity of cells.^[12]

In addition to RTK pathway,fibroblast growth factors can also activate theJAK-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 forerythropoietin (important forerythropoiesis),thrombopoietin (important forplatelet formation), andinterferon (important for mediating immune cell function).^[13]

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 astranscription factors to alter gene expression.^[13] In particular, the STATs transcribe genes that aid in cell proliferation and survival – such as myc.^[14]

Phenotype and survival of mice after knockout of some JAK or STAT genes:^[15]

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) andachondroplasic dwarfism (viable).^[16] This is due to a mutation in aFgf gene, causing a premature and constitutive activation of theStat1 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.^[17]

Research on paracrine signaling through the JAK-STAT pathway revealed its potential in activating invasive behavior of ovarianepithelial cells. This epithelial tomesenchymal transition is highly evident inmetastasis.^[18] 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.^[19]

TheHedgehog 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 inDrosophila. Hedgehog proteins produce key signals for the establishment of limb andbody plan of fruit flies as well ashomeostasis of adult tissues, involved in lateembryogenesis andmetamorphosis. At least three "Drosophila" hedgehoghomologs have been found in vertebrates: sonic hedgehog, desert hedgehog, and Indian hedgehog. Sonic hedgehog (SHH) has various roles in vertebrae development, mediating signaling and regulating the organization of central nervous system, limb, andsomitepolarity. Desert hedgehog (DHH) is expressed in theSertoli cells involved inspermatogenesis. Indian hedgehog (IHH) is expressed in the gut and cartilage, important in postnatal bone growth.^[20][21][22]

Members of the Hedgehog protein family act by binding to atransmembrane "Patched" receptor, which is bound to the "Smoothened" protein, by which the Hedgehog signal can betransduced. In the absence of Hedgehog, the Patched receptor inhibits Smoothened action. Inhibition of Smoothened causes theCubitus 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 transcriptionalrepressor. In the presence of Hedgehog, Patched no longer inhibits Smoothened. Then active Smoothened protein is able to inhibitPKA 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 transcriptionalactivator, inducing the expression of Hedgehog-response genes.^[22][23][24]

The Hedgehog Signaling pathway is critical in proper tissue patterning and orientation during normal development of most animals. Hedgehog proteins inducecell proliferation in certain cells and differentiations in others. Aberrant activation of the Hedgehog pathway has been implicated in several types ofcancers,Basal Cell Carcinoma in particular. This uncontrolled activation of the Hedgehog proteins can be caused by mutations to the signal pathway, which would beligand independent, or a mutation that causesoverexpression 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 afterandrogen deprivation therapy.^[25] 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 ofstem-cell populations, and required for normal growth and regeneration of damaged organs. This may provide another possible route fortumorigenesis via the Hedgehog pathway.^[26][27][28]

TheWnt protein family includes a large number ofcysteine-richglycoproteins. The Wnt proteins activatesignal transduction cascades via three different pathways, the canonicalWnt pathway, the noncanonicalplanar cell polarity (PCP) pathway, and the noncanonical Wnt/Ca²⁺ pathway. Wnt proteins appear to control a wide range of developmental processes and have been seen as necessary for control ofspindle 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 regulatedcell proliferation, cell morphology, cellmotility, and cell fate.^[29]

In thecanonical pathway, Wnt proteins binds to its transmembrane receptor of theFrizzled family of proteins. The binding of Wnt to a Frizzled protein activates theDishevelled 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 theAPC protein, which results inβ-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/Tcftranscription 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.^[30][31][32]

The noncanonical Wnt pathways provide a signal transduction pathway for Wnt that does not involveβ-catenin. In the noncanonical pathways, Wnt affects theactin andmicrotubularcytoskeleton as well asgene transcription.

The noncanonical PCP pathway regulates cellmorphology,division, andmovement. Once again Wnt proteins binds to and activates Frizzled so that Frizzled activates a Dishevelled protein that is tethered to the plasma membrane through aPrickle protein and transmembrane Stbm protein. The active Dishevelled activates RhoAGTPase through Dishevelled associated activator ofmorphogenesis 1 (Daam1) and theRac 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.^[30][31][32]

The noncanonical Wnt/Ca²⁺ pathway regulates intracellularcalcium levels. Again Wnt binds and activates to Frizzled. In this case however activated Frizzled causes a coupled G-protein to activate aphospholipase (PLC), which interacts with and splits PIP₂ into DAG and IP₃. IP₃ can then bind to a receptor on theendoplasmic reticulum to release intracellular calcium stores, to induce calcium-dependent gene expression.^[30][31][32]

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 humandegenerative disease andcancer.

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.^[33][34][35]

"TGF" (Transforming Growth Factor) is a family of proteins that includes 33 members that encodedimeric, secreted polypeptides that regulate development.^[36] Many developmental processes are under its control including gastrulation, axis symmetry of the body, organ morphogenesis, and tissue homeostasis in adults.^[37] AllTGF-β ligands bind to either Type I or Type II receptors, to create heterotetramic complexes.^[38]

TheTGF-β pathway regulates many cellular processes in developing embryo and adult organisms, includingcell growth,differentiation,apoptosis, andhomeostasis. 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 strongserine/threonine kinase activity.^[39] 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.^[40] This forms an activation complex that can then phosphorylate SMAD proteins.

There are three classes of SMADs:

1. Receptor-regulated SMAD (R-SMAD)
2. Common-mediator SMAD (Co-SMAD)
3. Inhibitory SMAD (I-SMAD)

Examples of SMADs in each class:^[41][42][43]

The TGF-β superfamily activates members of theSMAD family, which function as transcription factors. Specifically, the type I receptor, activated by the type II receptor, phosphorylatesR-SMADs that then bind to the co-SMAD,SMAD4. The R-SMAD/Co-SMAD forms a complex withimportin and enters the nucleus, where they act astranscription factors 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 SMAD1/5R-SMADs. For instance, whenactivin,Nodal, orTGF-β ligand binds to the receptors, thephosphorylated receptor complex can activateSMAD2 andSMAD3 through phosphorylation. However, when a BMP ligand binds to the receptors, the phosphorylated receptor complex activatesSMAD1 andSMAD5. Then, the Smad2/3 or the Smad1/5 complexes form a dimer complex withSMAD4 and becometranscription factors. Though there are manyR-SMADs involved in the pathway, there is only one co-SMAD,SMAD4.^[44]

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.^[45]

This family includesTGF-β1,TGF-β2,TGF-β3, and TGF-β5. They are involved in positively and negatively regulation ofcell division, the formation of theextracellular matrix between cells,apoptosis, andembryogenesis. They bind toTGF-β type II receptor (TGFBRII).

TGF-β1 stimulates the synthesis ofcollagen andfibronectin and inhibits the degradation of theextracellular matrix. Ultimately, it increases the production of extracellular matrix byepithelial cells.^[38]TGF-β proteins regulate epithelia by controlling where and when they branch to form kidney, lung, and salivary gland ducts.^[38]

Members of the BMP family were originally found to inducebone formation, as their name suggests. However, BMPs are very multifunctional and can also regulateapoptosis,cell migration,cell division, anddifferentiation. They also specify the anterior/posterior axis, induce growth, and regulatehomeostasis.^[36]

The BMPs bind to thebone morphogenetic protein receptor type II (BMPR2). Some of the proteins of theBMP family areBMP4 andBMP7.BMP4 promotes bone formation, causes cell death, or signals the formation ofepidermis, depending on the tissue it is acting on.BMP7 is crucial for kidney development, sperm synthesis, and neural tube polarization. BothBMP4 andBMP7 regulate mature ligand stability and processing, including degrading ligands in lysosomes.^[36] BMPs act by diffusing from the cells that create them.^[46]

• Vg1 Family
• Activin Family
  • Involved inembryogenesis andosteogenesis
  • Regulateinsulin andpituitary, gonadal, andhypothalamic hormones
  • Nerve cell survival factors
  • 3 Activins:Activin A,Activin B andActivin AB.
• Glial-Derived Neurotrophic Factor (GDNF)
  • Needed for kidney andenteric neurondifferentiation
• Müllerian Inhibitory Factor
  • Involved in mammalian sex determination
• Nodal
  • Binds toActivin A Type 2B receptor
  • Forms receptor complex withActivin A Type 1B receptor or withActivin A Type 1C receptor.^[47]
• Growth and differentiation factors (GDFs)

Growth factor andclotting factors 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 ofvitamin A, functions in a paracrine fashion to regulate gene expression during embryonic development in higher animals.^[48] In insects,Allatostatin controls growth through paracrine action on the corpora allata.^{[citation needed]}

In mature organisms, paracrine signaling is involved in responses toallergens, tissue repair, the formation ofscar tissue, and bloodclotting.^{[citation needed]}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.^[49]

• 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 signaling pathway
• Netpath – A curated resource of signal transduction pathways in humans
• Paracrine regulator

• Paracrine+Signaling at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
• "paracrine" atDorland's Medical Dictionary

• Signal transduction

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