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Paracrine signaling is a form of cell signaling in which the target cell is near ("para" = near) the signal-releasing cell.

Local action

Some signalling molecules degrade very quickly, limiting the scope of their effectiveness to the immediate surroundings. Others affect only nearby cells because they are taken up quickly, leaving few to travel further, or because their movement is hindered by the extracellular-matrix. Paracrine molecules must not be allowed to diffuse too far.

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 stimulate cell functions such as proliferation and differentiation. To fulfill these functions, FGFs are alternatively spliced or have different initiation codons to create hundred of different isoforms.

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. 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.

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.

Phenotype and survival of mice after knockout of some FGFR genes:

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.

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. 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.

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.

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

RTK receptor and cancer

Paracrine signaling of growth factors between nearby cells can 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 stem cell factor (SCF), which is important in hematopoiesis (formation of cells in blood). 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 malignancies.

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. Effectively, multiple bindings of ligands to the RTK receptors overstimulates the Ras-Maf-MAP pathway, which overexpresses the mitogenic and invasive capacity of cells.

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).

After dimerization of the cytokine receptors following ligand binding, the Jaks transphosphorylate each other. The resulting phosphotyrosines attract STAT proteins. T°he STAT proteins dimerize and enter the nucleus to act as transcription factors to alter gene expression. In particular, the STATS transcribe genes that aid in cell proliferation and survival -such as myc.

Phenotype and survival of mice after knockout of some Jak or STAT genes:

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 a severe form of dwarfism: thanatophoric dysplasia (lethal) and achondroplasic dwarfism (viable). 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.

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. 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.

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. In insects, Allatostatin controls growth though paracrine action on the corpora allata.

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

See also

• Autocrine signalling
• Endocrine system
• Local hormone - either a paracrine hormone, or a hormone acting in both a paracrine and an endocrine fashion
• Paracrine regulator

External links

• Paracrine+Signaling at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Template:EMedicineDictionary
• "paracrine" at Dorland's Medical Dictionary
• . GPnotebook https://www.gpnotebook.co.uk/simplepage.cfm?ID=-1335164869. {{cite web}}: Missing or empty |title= (help)