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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.
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.
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.
To fulfill many diverse functions, FGFs can be alternatively spliced or even have different initiation codons to create hundreds of different FGF isoforms.
One of the most important functions of the FGF receptors (FGFR) is in limb development.
This signaling involves nine different alternatively spliced isoforms of the receptor.
"Fgf"8 and "Fgf"10 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 "Tbx"5, which subsequently signals to the same mesoderm to produce "Fgf"10.
"Fgf"10 then signals to the ectoderm to begin production of "Fgf"8, which also stimulates the production of "Fgf"10.
Deletion of "Fgf"10 results in limbless mice.
Additionally, paracrine signaling of Fgf is essential in the developing eye of chicks.
The "fgf"8 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:
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 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.
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.
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.
An 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 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.
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).
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.
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.
Effectively, multiple bindings of ligands to the RTK receptors overstimulates the Ras-Raf-MAPK pathway, which overexpresses the mitogenic and invasive capacity of cells.
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).
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.
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:
The Jak-STAT 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: thanatophoric dysplasia (lethal) and achondroplasic dwarfism (viable).
This is due to a mutation in a Fgf gene, causing a premature and constitutive activation of the 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.
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.
The Hedgehog protein family is involved in induction of cell types and the creation of tissue boundaries and patterning and are found in all bilateral organisms.
Hedgehog proteins were first discovered and studied in "Drosophila".
Hedgehog proteins produce key signals for the establishment of limb and body plan of fruit flies as well as homeostasis of adult tissues, involved in late embryogenesis and metamorphosis.
At least three "Drosophila" hedgehog homologs have been found in vertebrates: sonic hedgehog, desert hedgehog, and Indian hedgehog.
Sonic hedgehog (SHH) has various roles in vertebrae development, mediating signaling and regulating the organization of central nervous system, limb, and somite polarity.
Desert hedgehog (DHH) is expressed in the Sertoli cells involved in spermatogenesis.
Indian hedgehog (IHH) is expressed in the gut and cartilage, important in postnatal bone growth.
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.
The Hedgehog Signaling pathway is critical in proper tissue patterning and orientation during normal development of most animals.
Hedgehog proteins induce cell proliferation in certain cells and differentiations in others.
Aberrant activation of the Hedgehog pathway has been implicated in several types of cancers, Basal Cell Carcinoma in particular.
This uncontrolled activation of the Hedgehog proteins can be caused by mutations to the signal pathway, which would be ligand independent, or a mutation that causes overexpression of the Hedgehog protein, which would be ligand dependent.
In addition, therapy-induced Hedgehog pathway activation has been shown to be necessary for progression of Prostate Cancer tumors after androgen deprivation therapy.
This connection between the Hedgehog signaling pathway and human cancers may provide for the possible of therapeutic intervention as treatment for such cancers.
The Hedgehog signaling pathway is also involved in normal regulation of stem-cell populations, and required for normal growth and regeneration of damaged organs.
This may provide another possible route for tumorigenesis via the Hedgehog pathway.
The Wnt protein family includes a large number of cysteine-rich glycoproteins.
The Wnt proteins activate signal transduction cascades via three different pathways, the canonical Wnt pathway, the noncanonical planar cell polarity (PCP) pathway, and the noncanonical Wnt/Ca 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.
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 Dishevelled protein.
In its active state the Dishevelled 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.
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 PCP pathway regulates cell morphology, division, and movement.
Once again Wnt proteins binds to and activates Frizzled so that Frizzled activates a Dishevelled protein that is tethered to the plasma membrane through a Prickle protein and transmembrane Stbm protein.
The active Dishevelled activates RhoA GTPase through Dishevelled associated activator of morphogenesis 1 (Daam1) and the 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.
The noncanonical Wnt/Ca pathway regulates intracellular calcium levels.