Editing Paracrine signaling (section)

===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>