Paracrine signaling

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In

extracellular
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.

Overview of signal transduction pathways.

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.[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, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.

Paracrine factors induce competent responders

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

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.

isoforms.[4]

One of the most important functions of the FGF receptors (FGFR) is in limb development. This signaling involves nine different

isoforms of the receptor.[5] Fgf8 and Fgf10 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 Tbx5, which subsequently signals to the same mesoderm to produce Fgf10. Fgf10 then signals to the ectoderm to begin production of Fgf8, which also stimulates the production of Fgf10. Deletion of Fgf10 results in limbless mice.[6]

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.[4]

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

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

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.[7]

Binding of FGF to FGFR

homodimerized 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.[8]

An

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.[9]

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

hematopoiesis (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]

RTK pathway and cancer

Research on

overexpresses the mitogenic and invasive capacity of cells.[13]

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).[14]

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.[14] In particular, the STATs transcribe genes that aid in cell proliferation and survival – such as myc.[15]

Phenotype and survival of mice after knockout of some JAK or STAT genes:[16]

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:

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.[18]

JAK-STAT pathway and cancer

Research on paracrine signaling through the JAK-STAT pathway revealed its potential in activating invasive behavior of ovarian

mesenchymal transition is highly evident in metastasis.[19] 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.[20]

Hedgehog family

The

IHH) is expressed in the gut and cartilage, important in postnatal bone growth.[21][22][23]

Hedgehog signaling pathway

Production of the CiR transcriptional repressor when Hh is not bound to Patched. In the diagram, "P" represents phosphate.
When Hh is bound to Patched (PTCH), Ci protein is able to act as a transcription factor in the nucleus.

Members of the Hedgehog protein family act by binding to a

transmembrane "Patched" receptor, which is bound to the "Smoothened" protein, by which the Hedgehog signal can be transduced. In the absence of Hedgehog, the Patched receptor inhibits Smoothened action. Inhibition of Smoothened causes the Cubitus 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 transcriptional repressor. In the presence of Hedgehog, Patched no longer inhibits Smoothened. Then active Smoothened protein is able to inhibit PKA 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 transcriptional activator, inducing the expression of Hedgehog-response genes.[23][24][25]

Hedgehog signaling pathway and cancer

The Hedgehog Signaling pathway is critical in proper tissue patterning and orientation during normal development of most animals. Hedgehog proteins induce

tumorigenesis via the Hedgehog pathway.[27][28][29]

Wnt family

Figure of the three main pathways of Wnt signaling in biological signal transduction.

The

Wnt pathway, the noncanonical planar 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 of spindle 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 regulated cell proliferation, cell morphology, cell motility, and cell fate.[30]

The canonical Wnt signaling pathway

Canonical Wnt pathway without Wnt.

In the

β-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/Tcf transcription 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.[31][32][33]

The noncanonical Wnt signaling pathways

The noncanonical Wnt pathways provide a signal transduction pathway for Wnt that does not involve

gene transcription
.

The noncanonical planar cell polarity (PCP) pathway

Noncanonical Wnt Planar Cell Polarity pathway.

The noncanonical PCP pathway regulates cell

Rac 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.[31][32][33]

The noncanonical Wnt/Ca2+ pathway

Noncanonical Wnt/calcium pathway.

The noncanonical Wnt/Ca2+ pathway regulates intracellular calcium levels. Again Wnt binds and activates to Frizzled. In this case however activated Frizzled causes a coupled G-protein to activate a phospholipase (PLC), which interacts with and splits PIP2 into DAG and IP3. IP3 can then bind to a receptor on the endoplasmic reticulum to release intracellular calcium stores, to induce calcium-dependent gene expression.[31][32][33]

Wnt signaling pathways and cancer

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 human degenerative disease and cancer.

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.[34][35][36]

TGF-β superfamily

"

TGF-β ligands bind to either Type I or Type II receptors, to create heterotetramic complexes.[39]

TGF-β pathway

The TGF-β pathway regulates many cellular processes in developing embryo and adult organisms, including cell growth, differentiation, apoptosis, and homeostasis. 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 strong serine/threonine kinase activity.[40] 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.[41] This forms an activation complex that can then phosphorylate SMAD proteins.

SMAD Signaling Pathway Activated by TGF-β

SMAD pathway

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:[42][43][44]

Class SMADs
R-SMAD SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8/9
Co-SMAD SMAD4
I-SMAD SMAD6 and SMAD7

The TGF-β superfamily activates members of the SMAD family, which function as transcription factors. Specifically, the type I receptor, activated by the type II receptor, phosphorylates R-SMADs that then bind to the co-SMAD, SMAD4. The R-SMAD/Co-SMAD forms a complex with importin and enters the nucleus, where they act as transcription 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 SMAD1/5

transcription factors. Though there are many R-SMADs involved in the pathway, there is only one co-SMAD, SMAD4.[45]

Non-SMAD pathway

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.[46]

Members of TGF-β superfamily

1. TGF-β family

This family includes

TGF-β type II receptor
(TGFBRII).

TGF-β1 stimulates the synthesis of

epithelial cells.[39]
TGF-β proteins regulate epithelia by controlling where and when they branch to form kidney, lung, and salivary gland ducts.[39]

2. Bone morphogenetic protein (BMPs) family

Members of the BMP family were originally found to induce

bone formation, as their name suggests. However, BMPs are very multifunctional and can also regulate apoptosis, cell migration, cell division, and differentiation. They also specify the anterior/posterior axis, induce growth, and regulate homeostasis.[37]

The BMPs bind to the

BMP7 regulate mature ligand stability and processing, including degrading ligands in lysosomes.[37] BMPs act by diffusing from the cells that create them.[47]

Other members of TGF-β superfamily

Summary table of TGF-β signaling pathway

TGF Beta superfamily ligand Type II Receptor Type I Receptor R-SMADs Co-SMAD Ligand Inhibitors
Activin A ACVR2A ACVR1B (ALK4)
SMAD3
SMAD4
 Follistatin
GDF1 ACVR2A ACVR1B (ALK4)
SMAD3
SMAD4
GDF11 ACVR2B
TGFβRI
(ALK5)
SMAD3
SMAD4
Bone morphogenetic proteins
 BMPR2 BMPR1A (ALK3), BMPR1B (ALK6)
SMAD8
SMAD4
DAN
Nodal
 ACVR2B ACVR1B (ALK4), ACVR1C (ALK7)
SMAD3
SMAD4
 Lefty
TGFβs
TGFβRII
TGFβRI
(ALK5)
SMAD3
SMAD4
THBS1, Decorin

Examples

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.[49]
In insects, Allatostatin controls growth through paracrine action on the corpora allata.[citation needed]


In mature organisms, paracrine signaling is involved in responses to

clotting.[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.[50]

See also

References

  1. ^ "Paracrine Factors". Retrieved 27 July 2018.
  2. PMID 2440668
    .
  3. PMID 2545723
    .
  4. ^
    PMID 8562905
    .
  5. ^
    PMID 8663044
    .
  6. PMID 14660539
    .
  7. ^
    PMID 7688944
    .
  8. PMID 3052279
    .
  9. PMID 9024640
    .
  10. S2CID 39924379
    .
  11. S2CID 2602233
    .
  12. PMID 15761501
    .
  13. PMID 11023813
    .
  14. ^
    S2CID 20857536
    .
  15. PMID 15020666
    .
  16. PMID 11983158
    .
  17. PMID 8723101
    .
  18. S2CID 20325070
    .
  19. PMID 19487818
    .
  20. PMID 11779460
    .
  21. PMID 11731473
    .
  22. PMID 7589793
    .
  23. ^
    S2CID 35653781
    .
  24. PMID 9729722
    .
  25. PMID 12200154
    .
  26. S2CID 2354209
    .
  27. PMID 15744048
    .
  28. PMID 17062662
    .
  29. S2CID 4414768
    .
  30. PMID 9407023
    .
  31. ^
    PMID 9425102
    .
  32. ^
    PMID 18604449
    .
  33. ^
    PMID 19279717
    .
  34. PMID 15473860
    .
  35. S2CID 28959851
    .
  36. S2CID 25793825
    .
  37. ^
    PMID 17194222
    .
  38. S2CID 84138159
    .
  39. ^
    ISBN 978-0-87969-752-5
    .
  40. ISBN 978-1-4020-4709-1
    .
  41. PMID 12154066
    .
  42. PMID 11779503
    .
  43. PMID 9214508
    .
  44. PMID 11483516
    .
  45. S2CID 131895
    .
  46. PMID 16105881
    .
  47. PMID 11839272
    .
  48. PMID 15150278
    .
  49. PMID 18805086
    .
  50. ISBN 978-1-947172-04-3
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Paracrine_signaling&oldid=1188199957"