Introduction of Fibroblast growth factors (FGF)

Fibroblast growth factors (FGF), which was first discovered in pituitary extracts in 1973,is widely expressed in cells and tissues. The FGF family is one of the largest growth factor families, consisting of 22 members sharing 13–71% sequence similarity in mammals. FGFs possess a large range of activities in embryonic development and physiological functions in the adult. In the embryo, FGFs often signal across mesenchymal-epithelial boundaries, where they regulate organogenesis and pattern formation. The mammalian fibroblast growth factor receptor family has 4 members, FGFR1, FGFR2, FGFR3 and FGFR4. The FGFRs consist of three extracellular immunoglobulin-type domains (D1-D3), a single-span trans-membrane domain and an intracellular split tyrosine kinase domain. FGFs interact with the D2 and D3 domains, with the D3 interactions primarily responsible for ligand-binding specificity (see below). Heparan sulfate binding is mediated through the D3 domain. A short stretch of acidic amino acids located between the D1 and D2 domains has auto-inhibitory functions. This 'acid box' motif interacts with the heparan sulfate binding site to prevent receptor activation in the absence of FGFs. The signaling complex at the cell surface is believed to be a ternary complex formed between two identical FGF ligands, two identical FGFR subunits, and either one or two heparan sulfate chains.

 

Introduction of Epidermal Growth Factor (EGF)

The members of the EGF family are best known for their ability to stimulate cell growth and proliferation and are important for many developmental processes including promoting mitogenesis and differentiation of mesenchymal and epithelial cells. EGF family members are commonly grouped with respect to their structural homology and biological activity.All members contain one or more repeats of a conserved six cysteine-containing motif in their extracellular domain.These six cysteine residues are contained within a sequence of 35–40 amino acids CX7CX4–5CX10–13CXCX8GXRC (C, cysteine; G, glycine; R, arginine; X, any amino acid), and have the potential to form three intra-molecular disulfide bond pairings between C1–C3, C2–C4 and C5–C6 to produce three loops that are essential for high-affinity binding to the receptor. HB-EGF and amphiregulin also contains a region rich in basic amino acids residues within their Nterminal regions that is responsible for their heparin-binding ability.

Introduction of Insulin-like growth factors (IGFs)

The insulin-like growth factors (IGFs) were first identified over 50 years ago and it has been over 30 years since their receptors were discovered and characterized. Radiolabeling experiments eventually helped to identify the receptor for IGF1, and the first report of a role for IGF1R in human cancers was by Pollak et al. in 1987 who used competitive binding assays to identify specific docking sites for IGF1 in breast and colon tumor biopsy specimens.The IGF signaling system family itself is composed of the three ligands IGF-1, IGF-2, and insulin; three cell membrane receptors–type 1 and 2 IGF receptors (IGF-1R and IGF-2R) and the insulin receptor (IR); seven high-affinity binding proteins (IGFBP 1-7); and several associated proteins, namely IRS and shc. These lead to two main signaling cascades: the PI3K/Akt and Ras/Raf/MEK/ERK pathways, which ultimately result in suppressed apoptosis, cell proliferation and invasion, and enhanced cell survival. Other studies are beginning to uncover the important role the IGFs play in diseases such as cancer and diabetes, showing for instance that IGF-1 stimulates growth of both prostate and breast cancer cells. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses.

Introduction of Glial-Derived Neurotrophic Factor (GDNF) family

Glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN) constitute the GDNF family of neurotrophic factors, which belongs to the transforming growth factor-β superfamily. The members of the GDNF family appear to play crucial roles in the development, differentiation and maintenance of various populations of vertebrate neurons. Biological actions of the GDNF family members are mediated via a multicomponent receptor complex, which consists of glycosylphosphatidylinositol (GPI)-linked ligand-binding a-components, designated GDNF family receptor alpha (GFRa) 1 through 4, and the signal transducing receptor tyrosine kinase Ret. The most prominent feature of GDNF is its ability to support the survival of dopaminergic and motorneurons. These neuronal populations die in the course of Parkinson's disease and amyotrophic lateral sclerosis (ALS). GDNF also regulates kidney development and spermatogenesis, and it affects alcohol consumption.

Introduction of Colony-stimulating factors (CSFs)

Colony-stimulating factors (CSFs) are secreted glycoproteins.  macrophage colonystimulating factor (M-CSF; also known as CSF1),Granulocyte/macrophage colony-stimulating factor (GM-CSF; also known as CSF2) and granulocyte colony-stimulating factor (G-CSF; also known as CSF3) were first defined by their abilities to generate in vitro colonies of mature myeloid cells from bone-marrow precursor cells following the proliferation and differentiation of these cells — granulocytic and macrophage colonies in the case of GM‑CSF, macrophage colonies for M‑CSF and granulocytic colonies for G‑CSF. It later became clear that these CSFs could also act in vitro on mature myeloid cells and therefore might have broader roles in an immune response than acting simply as haematopoietic-cell growth factors.

Introduction of the Tumor Necrosis Factor (TNF) superfamily

The tumor necrosis factor (TNF) superfamily, composed of 19 ligands and 29 receptors, plays highly diversified roles in the body. All members of the TNF superfamily, without exception, exhibit pro-inflammatory activity, in part through activation of the transcription factor NF-κB. Several members of the TNF superfamily exhibit proliferative activity on hematopoietic cells, in part through activation of various mitogen-activated kinases, and some members of this family play a role in apoptosis. Some members of the TNF superfamily have also been reported to play a role in morphogenetic changes and differentiation. Most members of the TNF superfamily have both beneficial and potentially harmful effects.

Introduction of Growth factors

Growth factors are proteins that function as growth stimulators and/or growth inhibitors, stimulate cell migration, act as chemotactic agents, inhibit cell migration, inhibit invasion of tumor cells, modulate differentiated functions of cells, involved in apoptosis, involved in angiogenesis and promote survival of cells without influencing growth and differentiation. Their activities are mediated via binding to transmembrane receptors that often contain cytoplasmic tyrosine kinase domains. When unregulated, many growth factors and their receptors have been implicated in tumor formation. Here are many families, which are listed below:

• Platelet-Derived Growth Factor Family
• Vascular Endothelial Growth Factor Family
• Epidermal Growth Factor Family
• Fibroblast Growth Factor Family
• Insulin-like growth factor Family
• Neurotrophin Family
• GDNF Family
• transforming growth factor-β Family

 

 

Introduction of Type III Interferon

Similar to the type I IFNs, the type III IFNs signal as monomeric cytokines engaging one copy of each of their low-affinity and high affinity receptors. However, unlike both the type I and type II IFNs, which employ their own dedicated receptors, the IFNλs utilize one unique receptor (IFNLR1) but also one required for signal transduction by IL-10, IL-22 and IL-26 (IL10RB). The receptor-associated JAK kinases, JAK1 with IFNLR1 and Tyk2 with IL10RB are responsible for activation of the JAK/STAT pathway upon IFNl engagement of this receptor complex. As IL10RB is also common to the signaling complexes for IL-10, IL-22 and IL-26, it remains to be seen whether there is any functional cross-talk between the type III IFNs and these cytokines as a result of having a shared receptor.

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