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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, altering the behavior or differentiation of 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 major families based on similar structures. They are the fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TFG-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.

Developmentalbio (talk) 23:37, 2 April 2013 (UTC)

Paracrine Factors Induce Competent Responders

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In order for paracrine factors to successfully induce a response in the receiving cell, that cell must be competent -meaning that the appropriate receptors must be available on the cell membrane to receive the signals. Additionally, the responding cell must also have the ability to be mechanistically induced.

Developmentalbio (talk) 23:37, 2 April 2013 (UTC)

Fibroblast Growth Factor (FGF) Family

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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

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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

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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

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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

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In addition to RTK pathway, fibroblast growth factors can also activate the Jak-STAT signaling cascade. 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).[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

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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 growth plate cells do not get transcribed. Thus, the inability of the rib cage to expand prevents the newborn's breathing.[17]

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

Jak-STAT pathway and Cancer

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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)

Hedgehog Family

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The Hedgehog protein family is involved in induction of cell types and the creation of tissue boundaries and patterning. Hedgehog proteins were first discovered and studied in Drosophila. Hedgehog proteins produce key signals for the establishment of limb and body plan of fuit flies. At least three to "Drosophila" hedgehog homologs have been found in vertebrates: sonic hedgehog, desert hedgehog, and indian hedgehog. Sonic hedgehog (shh) has various roles in vertebrae development, mediaing signaling and regulating the organization of central nervous system, limb, and somite polarity. Desert hedgehog (dhh) is expressed in the Seritoli cells involved in spermatogenesis. Indian hedgehog (ihh) is expressed in the gut and cartilage, important in postnatal bone growth.

Hedgehog Signaling Pathway

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Hedgehog Signaling Pathway and Cancer

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Wnt Family

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The Wnt protein family includes a large number of cytosine-rich glycoproteins. The Wnt proteins activate signal transduction cascades via three different types of pathways, the canonical Wnt pathway, the noncanonical planar cell polarity (PCP) pathway, and the noncanonical Wnt/Ca2+ pathway. The no 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. [20]

The Canonical Wnt Pathway

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In the canonical pathway, Wnt proteins binds to its transmembrane receptor of the Frizzled family of proteins. The binding of Wnt to a Frizzled protein activates the Disheveled protein. In its active state the Disheveled protein inhibits the activity of the glycogen synthase kinase 3 (GSK3) enzyme. Normally active GSK3 prevents the dissociation of β-catenin to the APC protein, which results in 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. [21] [22] [23]

The Noncanonical Wnt Pathways

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The noncanonical Wnt pathways provide a signal transduction pathway for Wnt that does not involve β-catenin. In the noncanonical pathways, Wnt affects the actin and microtubular cytoskeleton as well as gene transcription.

The Noncanonical Planar Cell Polarity (PCP) Pathway

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The noncanonical PCP pathway regulates cell morphology, dvision, and movement. Once again Wnt proteins binds to and activates Frizzled so that Frizzled activates a Disheveled protein that is tethered to the plasma membrane through a Prickle protein and transmembrane Stbm protein. The active Disheveled activates RohA GTPase through Disheveled associated activator of morphogenesis 1 (Daam1) and the Rac protein. Active RohA 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. [24] [25] [26]

The Noncanonical Wnt/Ca2+ Pathway

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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. [27] [28] [29]

Wnt Signaling Pathways and Cancer

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The Wnt signaling pathways are critical in cell-cell singling during normal development and embryogenesis and required for maintenance of adult tissue, therefore it is not difficult to understad why disruption in Wnt signaling pathways can promote human degenerative disease and cancer.

The Wnt signaling pathways are complex, involving many different elements, thus many targets for misregulation. Mutations that cause the constitutive activation of the Wnt signaling pathway lead to tumor formation and cancer. Aberant activation of the wint pathway can lead to increase cell proliferation. Current research is focused on the action of the Wnt signaling pathway on the fate of stem cells, regulating the 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. [30] [31] [32]

chingla 02:02, 3 April 2013 (UTC)

TGF-β Superfamily

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“TGF” stands for “Transforming Growth Factor,” and the family includes 33 members that encode dimeric, secreted polypeptides that regulate development.[33] Some developmental processes it controls include gastrulation, axis symmetry of the body, organ morphogenesis, and tissue homeostasis in adults.[34]

All TGF-β ligands bind to either Type I or Type II receptors, to create heterotetramic complexes.[35]

Jeenah92 (talk) 06:05, 2 April 2013 (UTC)

TGF-β Pathway

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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.[36] 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.[37] This forms an activation complex that can then phosphorylate SMAD proteins through phosphorylation.

Jeenah92 (talk) 06:05, 2 April 2013 (UTC)

File:Smad signaling pathway.png
SMAD Signaling Pathway Activated by TGF-β

SMAD Pathway

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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:[38] [39] [40]

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 R-SMADs. For instance, when activin, Nodal, or TGF-β ligand binds to the receptors, the phosphorylated receptor complex can activate SMAD2 and SMAD3 through phosphorylation. However, when a BMP ligand binds to the receptors, the phosphorylated receptor complex activates SMAD1 and SMAD5. Then, the Smad2/3 or the Smad1/5 complexes form a dimer complex with SMAD4 and become transcription factors. Though there are many R-SMADs involved in the pathway, there is only one co-SMAD, SMAD4.[41]

Jeenah92 (talk) 06:05, 2 April 2013 (UTC)

Non-SMAD Pathway

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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 with other signaling proteins, such as kinases. Finally, the TGF-β receptors directly phosphorylate non-Smad proteins.[42]

Members of TGF-β Superfamily

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1. TGF-β Family

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This family includes TGF-β1, TGF-β2, TGF-β3, and TGF-β5. They are involved in positively and negatively regulation of cell division, the formation of the extracellular matrix between cells, apoptosis, and embryogenesis. They bind to TGF-β type II receptor (TGFBRII).

TGF-β1 stimulates the synthesis of collagen and fibronectin and inhibits the degradation of the extracellular matrix degradation. Ultimately, it increases the production of extracellular matrix by epithelial cells.[43] TGF-β proteins regulate epithelia by controlling where and when they branch to form kidney, lung, and salivary gland ducts.[44]

Jeenah92 (talk) 06:05, 2 April 2013 (UTC)

2. Bone Morphogenetic Protein (BMPs) Family

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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 homeostatis.[45]

The BMPs bind to the bone morphogenetic protein receptor type II (BMPR2). Some of the proteins of the BMP family are BMP4 and BMP7. BMP4 promotes bone formation, causes cell death, or signals the formation of epidermis, depending on the tissue it is acting on. BMP7 is crucial for kidney development, sperm synthesis, and neural tube polarization. Both BMP4 and BMP7 regulate mature ligand stability and processing, including degrading ligands in lysosomes.[46] BMPs act by diffusing from the cells that create them.[47]

Jeenah92 (talk) 06:05, 2 April 2013 (UTC)

Other Members of TFG-β Superfamily

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Jeenah92 (talk) 06:05, 2 April 2013 (UTC)

Summary table

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TGF Beta superfamily ligand Type II Receptor Type I Receptor R-SMADs Co-SMAD Ligand Inhibitors
Activin A ACVR2A ACVR1B (ALK4) SMAD2, SMAD3 SMAD4 Follistatin
GDF1 ACVR2A ACVR1B (ALK4) SMAD2, SMAD3 SMAD4
GDF11 ACVR2B ACVR1B (ALK4), TGFβRI (ALK5) SMAD2, SMAD3 SMAD4
Bone morphogenetic proteins BMPR2 BMPR1A (ALK3), BMPR1B (ALK6) SMAD1 SMAD5, SMAD8 SMAD4 Noggin, Chordin, DAN
Nodal ACVR2B ACVR1B (ALK4), ACVR1C (ALK7) SMAD2, SMAD3 SMAD4 Lefty
TGFβs TGFβRII TGFβRI (ALK5) SMAD2, SMAD3 SMAD4 LTBP1, THBS1, Decorin

Examples

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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.[49] 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

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References

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[edit]

Category:Signal transduction

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