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Paracrine signaling is a form of cell-cell communication in which a cell produces a signal to induce changes in nearby cells. These paracrine factors diffuse over a relatively short distance (local action), as opposed endocrine factors (hormones which travel considerably longer distances via the circulatory system) and juxtacrine interactions (autocrine signaling). In paracrine signaling, the target cell is near ("para" = near) the signal-releasing cell. Cells that produce paracrine factors secrete them into their immediate extracellular environment. The distance the factors travel distinguishes the type of signaling. 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 of receptors and pathways. In fact, different organs in the body -even between different species - are known to utilize a similar sets of paracrine factors in differential development. The highly conserved receptor and pathways the paracrine factors utilize can be organized into four structurally distinct families. They are the fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TFG-β superfamily.

Developmentalbio (talk) 21:31, 2 April 2013 (UTC)

Fibroblast Growth Factor (FGF) Family

Although the FGF family of paracrine factors have a broad range of functions, major findings support the idea that they primarily stimulate cell functions such as proliferation and differentiation. [1] [2]


To fulfill many diverse functions, FGFs can be alternatively spliced or even have different initiation codons to create hundred of different FGF isoforms. [3]

One of the most important functions of the FGF receptors (FGFR) is in limb development. This signaling actually involves nine different alternatively spliced isoforms of the receptor.[4] Fgf8 and Fgf10 are two of the critical players in limb development. For example, in the forelimb initiation and limb growth in mice, axial cues from the intermediate mesoderm produces Tbx5, which then subsequently signals to the same mesoderm to produce Fgf10. In turn, Fgf10 signals to the ectoderm to begin production of Fgf8, which also stimulates the production of Fgf10. This positive feedback loop of paracrine signaling is essential in the production of limbs. Deletion of Fgf10 results in limbless mice. [5]

File:Mouselimb.jpg
Development of limb in mice.

Additionally, paracrine signaling of Fgf is essential in the developing eye of chicks. The fgf8 mRNA becomes localized in what differentiates into the neural retina of the optic cup. These cells are in contact with the outer ectoderm cells, which will eventually become the lens. [5]


Phenotype and survival of mice after knockout of some FGFR genes[4]:

FGFR Knockout Gene Survival Phenotype
Fgf1 Viable Unclear
Fgf3 Viable Inner ear, skeletal (tail) differentiation
Fgf4 Lethal Inner cell mass proliferation
Fgf8 Lethal Gastrulation defect, CNS development, limb development
Fgf10 Lethal Development of multiple organs (including limbs, thymus, pituitary)
Fgf17 Viable Cerebellar Development

Developmentalbio (talk) 03:45, 2 April 2013 (UTC)

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. [6]

Binding of FGF to FGFR phosphorylates the previously idle kinase, which activates the RTK pathway. This pathway begins at the cell surface, where a ligand binds to its specific receptor. Ligands that can binds to RTKs include fibroblast growth factors, epidermal growth factors, platelet-derived growth factors, and stem cell factor. [6] This dimerizes the transmembrane receptor to another RTK receptor, which causes the autophosphorylation and subsequent conformational change of the homodimerized receptor. This conformational change activates the dormant kinase of each RTK on the tyrosine residue. Because 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 transphosphorylation of the cytoplasmic domain of the receptor. [7]

Then, an adaptor protein (such as SOS) recognizes the phosphorylated tyrosine on the receptor. This protein functions as a bridge which connects the RTK an intermediate protein (such as GNRP), starting the intracellular signaling cascade. In turn, the intermediate protein stimulates GDP-bound Ras to the activated to GTP-bound Ras. GAP eventually returns Ras to its inactive state. Activation of Ras has the potential to initiate three signaling pathways downstream of Ras: Ras→Raf→MAP kinase pathway, PI3 kinase pathway, and RaI pathway. Each pathway eventually activates transcription factors which enter the nucleus to alter gene expression. [8]

Developmentalbio (talk) 03:45, 2 April 2013 (UTC)

RTK receptor and cancer

Paracrine signaling of growth factors between nearby cells has been shown to exasperate carcinogenesis. In fact, mutant forms of a single RTK may play a causal role in very different types of cancer. For example, 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). [9] 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. [10]

Developmentalbio (talk) 04:21, 2 April 2013 (UTC)

RTK pathway and cancer

Research on thyroid cancer has eluciated 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. [11] Effectively, multiple bindings of ligands to the RTK receptors overstimulates the Ras-Maf-MAP pathway, which overexpresses the mitogenic and invasive capacity of cells. [12]

Developmentalbio (talk) 04:21, 2 April 2013 (UTC)

Jak-STAT Pathway

In addition to RTK pathway, fibroblast growth factors can also activate the Jak-STAT signaling cascade. Instead of carry 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). [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 as transcription 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]:

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

Developmentalbio (talk) 05:45, 2 April 2013 (UTC)

Abberant Jak-STAT Pathway: Bone Mutations

The Jak-STAT pathway is also incredibly instrumental in the development of limbs; this pathway regulates bone growth. Paracrine signaling of cytokines induce such developments. However, mutations in this pathway have been implicated in severe forms of dwarfism: thanatophoric dysplasia (lethal) and achondroplasic dwarfism (viable). [16] This is due to a mutation a Fgf gene, causing a premature and constitutive activation of the Stat1 transcription factor. Chondrocyte cell division gets prematurely terminated, resulting in lethal dwarfism. Rib and limb bone gorwth plate cells do not get transcribed. Thus, the inability of the thoracic cage to expand prevents the newborn's breathing. [17]

Developmentalbio (talk) 05:45, 2 April 2013 (UTC)

Jak-STAT pathway and Cancer

Research on paracrine signaling through the Jak-STAT pathway revealed its potential in activating invasive behavior of ovarian epithelial cells. This epithelial to mesenchymal transition is highly evident in metastasis. [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]

Developmentalbio (talk) 05:45, 2 April 2013 (UTC)

Examples

Growth factor and clotting 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 of vitamin A, functions in a paracrine fashion to regulate gene expression during embryonic development in higher animals.[20] In insects, Allatostatin controls growth though paracrine action on the corpora allata.[citation needed]

In mature organisms, paracrine signaling is involved in responses to allergens, tissue repair, the formation of scar tissue, and blood clotting.[citation needed]

See also

References

  1. ^ Gospodarowicz, D. (May 1987). "Structural Characterization and Biological Functions of Fibroblast Growth Factor". Endocrine Reviews. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  2. ^ Rifkin D.B. & Moscatelli D. (July 1989). "Recent Developments in the Cell Biology of Basic Fibroblast Growth Factor" (PDF). Mini-Review. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help); line feed character in |title= at position 41 (help)
  3. ^ Lappi D.A. (October 1995). "Tumor targeting through fibroblast growth factor receptors". Seminars in Cancer Biology. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  4. ^ a b Ornitz D.M. (June 1996). "Receptor Specificity of the Fibroblast Growth Factor Family". The Journal of Biological Chemistry. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help) Cite error: The named reference "Ornitz"" was defined multiple times with different content (see the help page).
  5. ^ a b Logan M. (December 2003). "Tumor targeting through fibroblast growth factor receptors". Development. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  6. ^ a b Fantl W.J., Johnson D.E., Williams L.T. (1993). "Signaling by receptor tyrosine kinases". Annual Reviews. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help); line feed character in |title= at position 22 (help)CS1 maint: multiple names: authors list (link)
  7. ^ Yarden Y. (1988). "Growth Factor Receptor Tyrosine". Annual Reviews of Biochemistry. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  8. ^ Katz M.E. & McCormick F. (February 1997). "Signal transduction from multiple Ras effectors". Current Opinion in Genetics & Development. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  9. ^ Zsebo K.M. (October 1990). "Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor". Cell. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  10. ^ Rönnstrand L. (April 2004). "Signal transduction via the stem cell factor receptor/c-Kit" (PDF). Cellular and Molecular Life Sciences. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  11. ^ Mellilo R.M. (April 2005). "The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells". The Journal of Clinical Investigation. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  12. ^ Kolch W. (April 2005). "Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions" (PDF). Biochemistry Journal. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help); line feed character in |title= at position 72 (help)
  13. ^ a b Aaronson D.S. & Horvath C.M. (May 2002). "A Road Map for Those Who Don't Know JAK-STAT". Science. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  14. ^ Rawlings S.J., Rosler K.M., Harrison D.A. (March 2004). "The JAK/STAT signaling pathway". Journal of Cell Science. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)CS1 maint: multiple names: authors list (link)
  15. ^ O’Shea J.J., Gadina M., Schreiber R.D. (April 2002). "Cytokine Signaling in 2002: New Surprises in the Jak/Stat Pathway" (PDF). Cell. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)CS1 maint: multiple names: authors list (link)
  16. ^ Bonaventure J., Rousseau, F., Legeai-Malle L., Le Merrer M., Munnich A., Maroteaux P. (1996). "Common Mutations in the Fibroblast Growth Factor Receptor 3 (FGFR 3) Gene Account for Achondroplasia, Hypochondroplasia, and Thanatophoric Dwarfism". Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help); Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  17. ^ Shiang R., Thompson L.M., Zhu Y., Church D.M., Fielder T.J., Bocian M., Winokur S.T., Wasmuth J.J. (June 1994). "Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia". Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help); Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  18. ^ Kalluri R. & Weinberg R.A. (2009). "The basics of epithelial-mesenchymal transition". The Journal of Clinical Investigation. Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help)
  19. ^ Silve D.L. & Montell D.J. (December 2001). "Paracrine Signaling through the JAK/STAT Pathway Activates Invasive Behavior of Ovarian Epithelial Cells in Drosophila". Retrieved 20013-04-01. {{cite journal}}: Check date values in: |accessdate= (help); Cite journal requires |journal= (help)
  20. ^ Duester, G (2008). "Retinoic acid synthesis and signaling during early organogenesis". Cell. 134 (6): 921–31. doi:10.1016/j.cell.2008.09.002. PMC 2632951. PMID 18805086. {{cite journal}}: Unknown parameter |month= ignored (help)
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