Editing Paracrine signaling (section)

==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>