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The 14-3-3 family of proteins plays a key regulatory role in signal transduction, checkpoint control, apoptotic and nutrient-sensing pathways. 14-3-3 proteins are highly conserved and ubiquitously expressed. There are at least seven isoforms that have been identified in mammals. The 14-3-3gamma, a subtype of the 14-3-3 family of proteins, was thought to be brain and neuron-specific. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways.

MVK is a member of the GHMP kinase family. Mevalonate is a vital mediator, and MVK an important early enzyme, in isoprenoid and sterol synthesis. MVK deficiency can result in gene mutation associated with Mevalonic aciduria, an illness which causes psychomotor retardation, failure to thrive hepatosplenomegaly, anemia and frequent febrile crises. Mutations in this gene also cause hyperimmunoglobulinaemia D and sporadic fever syndrome, in which the person suffers from recurrent episodes of fever related with lymphadenopathy, skin rash, gastrointestinal dismay and arthralgia.

Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. TNF is mainly secreted by macrophages.
TNF causes apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesisand viral replication, TNF is also involved in lipid metabolism, and coagulation. TNF's primary role is in the regulation of immune cells.
Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases- autoimmune diseases, insulin resistance, and cancer.

IL11 is a member of the gp130 family of cytokines. These cytokines drive the assembly of multisubunit receptor complexes, all of which contain at least one molecule of the transmembrane signaling receptor IL6ST (gp130). IL-11 is shown to stimulate the T-cell-dependent development of immunoglobulin-producing B cells. It is also found to support the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells.

EIF1AX is an important eukaryotic translation initiation factor. EIF1AX is essential for the binding of the 43S complex (a 40S subunit, eIF2/GTP/Met-tRNAi and eIF3) to the 5'' end of capped RNA. EIF1AP1 is needed for maximal rate of protein biosynthesis. EIF1AX increases ribosome dissociation into subunits and stabilizes the binding of the initiator Met-tRNA (I) to 40 S ribosomal subunits.

Members of the Interferon regulatory factor (IRF) family regulate gene expression critical to immune response, hemopoiesis, and proliferation. IRF-3 is a member of the IRF family, and is distinct from other family members. Its transcriptional activity is regulated solely by posttranslational modifications. It plays a crucial role in activation of innate immunity and inflammation in response to viral infection. IRF-3 mediates interferon-stimulated response element (isre) promoter activation. Functions as a molecular switch for antiviral activity. Dsrna generated during the course of an viral infection leads to IRF3 phosphorylation on the c-terminal serine/threonine cluster. This induces a conformational change, leading to its dimerization, nuclear localization and association with creb binding protein (crebbp) to form dsrna-activated factor 1 (draf1), a complex which activates the transcription of genes under the control of isre. The complex binds to the ie and prdiii regions on the ifn

Chemokine (C-C motif) ligand 2 (CCL2) is a small cytokine belonging to the CC chemokine family that is also known as monocyte chemotactic protein-1 (MCP-1). It is found at the site of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature osteoclasts and osteoblasts and is under the control of nuclear factor ?B (NF?B). CCL2 recruits immune cells, such as monocytes, to sites of tissue injury and infection. This chemokine is produced as a protein precursor containing signal peptide of 23 amino acids and a mature peptide of 76 amino acids. It is a monomeric polypeptide, with a molecular weight of approximately 13kDa. As with many other CC chemokines, CCL2 is located on chromosome 17 in humans. The cell surface receptors that bind CCL2 are CCR2 and CCR5.

Interleukin-1 alpha is a proinflammatory cytokine produced by a wide variety of cell types, including macrophages, osteoblasts, monocytes and hepatocytes. Circulating levels of are normally low and only rise after stimulation by agents such as those produced byinflammation, infection or microbial endotoxins. IL-1 alpha possesses a wide variety of biological activities and exerts its effects by binding to specific cell surface receptors.

TNFRSF17 is a receptor for tnfsf13b/blys/baff and tnfsf13/april. TNFRSF17 promotes b-cell survival and plays a role in the regulation of humoral immunity. TNFRSF17 activates nf-kappa-b and jnk. TNFRSF17 is a member of the TNF-receptor superfamily. TNFRSF17 is expressed in mature B lymphocytes, and is invloved in B cell development and autoimmune response. TNFRSF17 specifically binds to the tumor TNFSF13B/TALL-1/BAFF, which causes NF-kappaB and MAPK8/JNK activation. TNFRSF17 binds to a variety of TRAF family members, and therefore transduces signals for cell survival and proliferation. TNFRSF17 is a type III membrane protein having 1 extracellular cysteine rich domain. Within the TNFRSF, it shares the highest homology with TACI. BCMA and TACI have both been shown to bind to APRIL and BAFF, members of the TNF ligand superfamily. BCMA expression has been found in immune organs. TNFRSF17 appears to be localized to the Golgi compartment. The binding of BCMA to APRIL or BAFF has been shown to stimulate IgM production in peripheral blood B cells and increase the survival of cultured B cells.

Inhibitor of DNA Binding 2 (ID2) is a part of the inhibitor of DNA binding family, whose members are transcriptional regulators that contain a helix-loop-helix (HLH) domain but not a basic domain. Members of the ID family inhibit the functions of basic helix-loop-helix transcription factors in a dominant-negative way by suppressing their heterodimerization partners through the HLH domains. ID2 play a role in negatively regulating cell differentiation and may be an inhibitor of tissue-specific gene expression.

Interleukin-1 ra is a member of the interleukin 1 cytokine family. IL1RAinhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses. IL1RAand five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer.

Chemokine (C-X-C motif) ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as Monokine induced by MIG. CXCL9 is a T-cell chemoattractant. It is closely related to two other CXC chemokines called CXCL10 and CXCL11, whose genes are located near the gene for CXCL9 on human chromosome 4. CXCL9, CXCL10 and CXCL11 all elicit their chemotactic functions by interacting with the chemokine receptor CXCR3.

Interleukin 10 or IL-10 or human cytokine synthesis inhibitory factor, is a cytokine (anti-inflammatory). IL10 gene is coding for il-10 In humans. Interleukin 10 has a receptor complex that is built from a couple of IL-10 receptor-1 and a couple of IL-10 receptor-2 proteins. therfore, the whole receptor unit consists of four IL-10 receptor molecules. IL-10 binds the receptor and causes STAT3 signalling through the phosphorylation of the cytoplasmic ends of IL-10 receptor 1 and IL-10 receptor 2 through JAK1 and Tyk2.

APIP catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P). APIP has an anti-apoptotic function and inhibits muscle ischemic impairment. APIP inhibits the cytochrome c-dependent and APAF1-mediated cell death.

MGP is vital for the regulation of calcification in the extracellular matrix, particularly in cartilage and arteries. The K-dependent vitamin MGP has five to six residues of Gla, a Ca2+ binding amino acid crucial for vitamin K-dependent gamma carboxylase for its formation. MGP is formed by COOH-terminal processing by carboxypeptidase B-like enzymatic activity and localized in the human bone.

Connective Tissue Growth Factor belongs to the CCN family of proteins. The CCN family presently consists of six members in human also known as: Cyr61 (Cystein rich 61), CTGF (Connective Tissue Growth Factor), Nov (Nephroblastoma Overexpressed gene), WISP-1, 2 and 3 (Wnt-1 Induced Secreted Proteins). The CCN genes encode secreted proteins associated with the Extracellular Matrix (ECM) and cell membrane.
CCN proteins are matricellular proteins which are involved in the regulation of various cellular functions including: proliferation, differentiation, survival, adhesion and migration. They are expressed in derivatives of the three embryonic sheets and are implicated in the development of kidney, nervous system, muscle, bone marrow, cartilage and bone. During adulthood, they are implicated in wound healing, bone fracture repair, and pathologies such as: fibrosis, vascular ailments and tumorigenesis.
Full length secreted CCN proteins can show an antiproliferative activity, whereas truncated isoforms are likely to stimulate proliferation and behave as oncogenes.
The full length protein consists of four modulesModule I shares partial identity with the N-terminal part of the Insulin-like Growth Factor Binding Proteins (IGFBPs).
Module II includes a stretch of 70amino acid residues – which shares sequence identity with the Von Willebrand Factor Type C repeat (VWC).
Module III contains sequences sharing identity with the Thrombospondin type 1 repeat (TSP1) (WSXCSXXCG), which is thought to be implicated in the binding of sulfated glycoconjugates and to be important for cell adhesion.
Module IV, also designated CT, is encoded by exon5. It is the leasts conserved one of the four domains at the level of nucleotide sequence, but it appears to be critical for several of the biological functions attributed to the CCN proteins. Module IV resembles the CT domain of several extracellular protein including, Von Willebrand's factor and mucins. Sequence similarities to heparin-binding motifs are also found within this domain.
Proteolysis of the secreted full-length CCN proteins that has been reported in the case of CCN2 and CCN3 might result in the production of CCN-derived peptides with high affinity for ligands that full-length CNN proteins bind only poorly. Amino-truncated CCN2 isoforms were biologically active whereas no specific biological activity has been attributed to the truncated CCN3. Although the molecular processes underlying the production of these secreted isoforms is presently unknown, it is important to note that proteolysis occur at the same amino acid residues in both CCN2 and CCN3. An elevated expression of CCN2 has also been detected by Northern blotting in human invasive mammary ductal carcinomas, dermatofibromas, pyogenic granuloma, endothelial cells of angiolipomas and angioleiomyomas, and in pancreatic tumors. A study performed with chondrosarcomas representative of various histological grades established that CCN2 expression was closely correlated with increasing levels of malignancy.
In agreement with CCN2 playing a role in brain tumor angiogenesis, immunocytochemistry studies indicated that both glioblastoma tumor cells and proliferating endothelial cells stained positive for CCN2. In astrocytomas, CCN2 expression was particularly elevated in high grade tumors, with a marked effect of CCN2 on cell proliferation. Downregulation of CCN2 expression in these cells was associated with a growth arrest at the G1/S transition while over-expression of CCN2 induced a two-fold increase of the number of cells in the G1 phase. Gene profiling analysis allowed to identify a set of about 50 genes whose expression might account for the proliferative activity of CCN2 in these cells.
CCN2 was seen in a higher proportion of mononuclear cells of patients with acute lymphoblastic leukemia.

GDF3 is a member of the TGF-beta superfamily though it does not show similarity pattern of conserved cysteine residues. GDF3 is linked to Vg-1 and human BMP-4. GDF3 transcripts are identified mainly in adult bone marrow, spleen, thymus, and adipose tissue. GDF3 expression is upregulated strongly in high-fat-fed C57Bl/6J FABP4/aP2 null mice, which develop obesity but not the related hyperglycemia or hyperinsulinemia characteristic of type II diabetes. GDF3 expression therefore bonds fatty acid metabolism in adipocytes and the expression of a differentiation regulator belonging to the bone morphogenetic proteins.

The Fas receptor (CD95) mediates apoptotic signaling by Fas-ligand expressed on the surface of other cells. The Fas-FasL interaction plays an important role in the immune system and lack of this system leads to autoimmunity, indicating that Fas-mediated apoptosis removes self-reactive lymphocytes. Fas signaling is also involved in immune surveillance to remove transformed cells and virus infected cells. Binding of FAS to oligimerized FasL on another cell activates apoptotic signaling through a cytoplasmic domain termed the death domain that interacts with signaling adaptors including FAF, FADD and DAX to activate the caspase proteolytic cascade. Caspase-8 and caspase-10 are first activated, to then cleave and activate downstream caspases, and a variety of cellular substrates that lead to cell death. Caspases cleave nuclear lamins, causing the nucleus to break down and lose its normal structure and another caspase substrate is DFF, inducing cleavage and degradation of the genome. Other caspase substrates are involved in cytoskeletal structure, cell cycle regulation and signaling pathways. Activation of JNK kinase, activation of Jun, and production of ceramide may also play roles in Fas-mediated apoptosis. Activation of fas-mediated apoptosis is opposed by I-FLICE and FAP. Viruses and tumors may escape immune surveillance in part through suppression of fas-mediated apoptosis using similar mechanisms.

Myeloid-derived growth factor (Mydgf) is a paracrine-acting protein and a bone marrow-derived monocyte which stimulates cardiac myocyte survival and adaptive angiogenesis for cardiac protection and repair after myocardial infarction. Mydgf induces endothelial cell proliferation through a MAPK1/3-, STAT3- and CCND1-mediated signaling lane. When comparing wild-type mice to mice with a Mydgf-deficiency, the later develop larger infarct scars and more acute contractile dysfunction.

GDF10 is a member of the BMP family and the TGF-beta superfamily. GDF10 is expressed in femur, brain, lung, skeletal, muscle, pancreas and testis, and has a role in head formation and possibly multiple roles in skeletal morphogenesis. In humans, GDF10 mRNA is found in the cochlea and lung of fetuses, and in testis, retina, pineal gland, and other neural tissues of adults. The BMP family members are regulators of cell growth and differentiation in both embryonic and adult tissues. These proteins are characterized by a polybasic proteolytic processing site which is cleaved to produce a mature protein containing 7 conserved cysteine residues.

Signal-Regulatory Protein Alpha, SIRPA belongs to the signal-regulatory-protein (SIRP) family, as well as the immunoglobulin super family. The members of the SIRP family are receptor-type transmembrane glycoproteins which are involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes.
SIRPA can be phosphorylated by tyrosine kinases. The phospho-tyrosine residues of this PTP have been shown to recruit SH2 domain containing tyrosine phosphatases (PTP), and perform as substrates of PTPs. SIRPA take part in signal transduction mediated by a variety of growth factor receptors. CD47 has been shown to be a ligand for SIRPA.

Plasma protease C1 inhibitor (SERPING1) is a part of the serpin superfamily of serine protease inhibitors. SERPING1 plays an important role in regulating activation of both the complement and contact systems. That isdue to the fact that SERPING1 regulates the activation of complement factor C1 in addition to the activity of activated C1 by coupling with the active catalytic site at the light chains of C1r and C1s. SERPING1 insufficiency results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa.

Tumor necrosis factor receptor superfamily member 8 (TNFRSF8) is a receptor for TNFSF8/CD30L. TNFRSF8 has a role in the regulation of cellular growth and transformation of activated lymphoblasts. In addition, the TNFRSF8 protein regulates gene expression via activation of NF-kappa-B. TNFRSF8 being a regulator of apoptosis, induces cell death or proliferation, depending on the cell type.

SDF-1 (stromal cell-derived factor-1) is small cytokine belonging to the chemokine family that is officially designated Chemokine (C-X-C motif) ligand 12 (CXCL12). It is produced in two forms, SDF-1?/CXCL12a and SDF-1?/CXCL12b, by alternate splicing of the same gene. Chemokines are characterized by the presence of four conserved cysteines, which form two disulfide bonds. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening amino acid. CXCL12 is strongly chemotactic for lymphocytes and has been implicated as an important cell co-ordinator during development. During embryogenesis it directs the migration of hematopoietic cells from foetal liver to bone marrow. Mice which were knocked-out for CXCL12 gene were lethal before the birth or within just 1 hour of life. As another role, CXCL12a alters also the electrophysiology of neurons. CXCL12 was shown to be expressend in many tissues in mice (including brain, thymus, heart, lung, liver, kidney, spleen and bone marrow).
The receptor for this chemokine is CXCR4, which was previously called fusin. This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently it was suggested that CXCL12 is also bound by CXCR7 receptor.
The gene for CXCL12 is located on human chromosome 10. In human and mouse both CXCL12 and CXCR4 show high identity of sequence: 99% and 90%, respectively.