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CALR is a multifunctional protein that acts as a main Ca(2+)-binding (storage) protein in the lumen of the endoplasmic reticulum. Calreticulin is localized in the nucleus, and participates in transcription regulation. Calreticulin binds to the synthetic peptide KLGFFKR, which is nearly identical to an amino acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. CALR binds to antibodies in specific sera of systemic lupus and Sjogren patients which have anti-Ro/SSA antibodies, it is well conserved among species, and it is positioned in the endoplasmic and sarcoplasmic reticulum where it binds calcium. The amino terminus of CALR interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. CALR reduces the binding of androgen receptor to its hormone-responsive DNA element and inhibits androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Therefore, CALR acts as a significant modulator of the regulation of gene transcription by nuclear hormone receptors.

Cytokeratin 8 (KRT8) belongs to the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. KRT8 typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. KRT8 has a role in retaining cellular structural integrity and also functions in signal transduction and cellular differentiation. KRT8 gene mutations cause cryptogenic cirrhosis.

GH is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature.

Clusterin also named Apolipoprotein J (APO-J) is a 75-80 kD disulfide-linked heterodimeric protein containing about 30% of N-linked carbohydrate rich in sialic acid but truncated forms targeted to the nucleus have also been identified.
The precursor polypeptide chain is cleaved proteolytically to remove the 22-mer secretory signal peptide and subsequently between residues 227/228 to generate the a and b chains. These are assembled in anti-parallel to give a heterodimeric molecule in which the cysteine-rich centers are linked by five disulfide bridges and are flanked by two predicted coiled-coil a-helices and three predicted amphipathic a-helices.
Across a broad range of species clusterin shows a high degree of sequence homology ranging from 70% to 80%. It is nearly ubiquitously expressed in most mammalian tissues and can be found in plasma, milk, urine, cerebrospinal fluid and semen.
It is able to bind and form complexes with numerous partners such as immunoglobulins, lipids, heparin, bacteria, complement components, paraoxonase, beta amyloid, leptin and others. Clusterin has been ascribed a plethora of functions such as phagocyte recruitment, aggregation induction, complement attack prevention, apoptosis inhibition, membrane remodeling, lipid transport, hormone transport and/or scavenging, matrix metalloproteinase inhibition.
A genuine function of clusterin has not been defined. One tempting hypothesis says that clusterin is an extracellular chaperone protecting cells from stress induced insults caused by degraded and misfolded protein precipitates.
Clusterin is up- or down regulated on the mRNA or protein level in many pathological and clinically relevant situations including cancer, organ regeneration, infection, Alzheimer disease, retinitis pigmentosa, myocardial infarction, renal tubular damage, autoimmunity and others.

Vaspin (visceral adipose-specific SERPIN) is a newly identified adipokine, which is a member of serine protease inhibitor family. Vaspin is also a unique insulin sensitizing adipocytokine in obesity. A recent publication indicates that induction of human vaspin mRNA expression in adipose tissue is regulated in a fat depot-specific manner and could be associated with parameters of obesity, insulin resistance, and glucose metabolism.

MANF is a 20kDa protein which belongs to the ARMET family. MANF was originally known as an arginine-rich region protein which was extremely mutated in a large number of tumors. MANF Expression is induced during ER stress, signifying that MANF takes part in protein quality control during ER stress.

Bronchoalveolar lavage fluid from mice with experimentally induced allergic pulmonary inflammation contains a novel 9.4 kDa cysteine-rich secreted protein, RELM-alpha (FIZZ1, found in inflammatory zone). RELM-alpha is a secreted protein that has a restricted tissue distribution with highest levels in adipose tissue stroma. Murine RELM-alpha (FIZZ1) is the founding member of a new gene family including two other murine genes expressed, respectively, in intestinal crypt epithelium (RELM-beta) and white adipose tissue (Resistin), and two related human genes.
RELMalpha inhibits the differentiation of 3T3-L1 preadipocytes into adipocytes but has no effect on proliferation of 3T3-L1 preadipocytes. RELMalpha is able to form heterooligomers with resistin but not RELMbeta. Since RELMalpha is expressed by adipose tissue and it is a secreted factor, our findings suggest that RELMalpha may be involved in the control of the adipogenesis as well as in the process of muscle differentiation.
In the lung, RELM-alpha is induced by hypoxia and was renamed as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 micromol/L) inhibited HIMF-activated Akt phosphorylation. It also inhibited HIMFstimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. Further studies showed that HIMF had angiogenic and vasoconstrictive properties. HIMF increased pulmonary arterial pressure and vascular resistance. Further studies suggest that HIMF regulates apoptosis and may participate in lung alveolarization and maturation.

Regulator of G-protein signaling 21 (RGS21) belongs to the RGS family and regulatory molecules which act as GTPase activating proteins for G alpha subunits of heterotrimeric G proteins. The RGS21 protein inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thus driving them into their inactive GDP-bound form.

Relaxin-3 (RLN3) belongs to the relaxin family. Relaxins are endocrine and autocrine/paracrine hormones. Relaxin, which is produced by the ovary, targets the mammalian reproductive system to ripen the cervix, elongate the pubic symphysis and inhibit uterine contraction. Unlike human Relaxins 1 and 2, Relaxin 3 does not seem to have a role in reproduction; however it is involved in stress response in the brain stem. RLN3 is the only known ligand for the G-protein-coupled receptor GPCR135, titled RXFP3. In addition, RLN3 binds the LGR7 (RXFP1) receptor, however with lower affinity than Relaxin-2. Even though binding of RLN3 to LGR7 increases intracellular cAMP, binding to GPCR135 suppresses cAMP accumulation, indicating coupling to Gi, Go, or Gz by this receptor.

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.

Neurotrophic Receptor Tyrosine Kinase 3 (NTRK3)belongs to the receptor tyrosine kinases family and is a high affinity catalytic receptor of neurotrophin NT-3. NTRK3 mediates multiple effects of this neurotrophic factor, which includes neuronal differentiation and survival. NTRK3 inducesvarious pleiotorpic responses in malignant cells, including enhanced tumor cell invasiveness and chemotoxis.Increased NTRK3 expression was observed in neuroblastoma, medulloblastoma, and in neuroectodermal brain tumors.

Agouti-related protein is an endogenous antagonist of hypothalamic alpha-melanocortin receptors MC3R and MC4R with potent orexigenic activity. Although a complete deletion of the AGRP gene does not produce any significant metabolic phenotypes, reduction in AGRP expression by RNA interference is associated with increased metabolic rate along with reduced weight gain. In hypothalamus, it is produced by neurons in the medial portion of arcuate nucleus, which produce also the potent orexigenic peptide Neuropeptide Y (NP-Y). Another site of central AGRP production is the hypothalamic nucleus. AGRP encompasses 132 amino acid residues and its alpha-melanocortin inhibiting activity results in a 34 amino acid cystine knot domain within the C-terminal (87-132) portion of the protein. Both AGRP and NP-Y expression was shown to be suppressed by leptin. Central administration of AGRP induces hyperphagia and increased gain in body weight in rodents, but may also exert metabolic effects even when hyperphagia is prevented. In the absence of hyperphagia, intracerebralventricular administration of AGRP caused significant increases in plasma leptin and insulin concentrations (twofold and 1.5-fold, respectively) and fat pad mass.
In the periphery, AGRP mRNA was found in adrenal glands, lung, testis, ovary, skeletal muscle and adipose tissue in humans or rodents. In the adrenals, it was shown that AGRP antagonizes glucosteroid production mediated by MC4R. AGRP could then modulate locally the functions of some peripheral tissues such as adrenals.
In human and rat serum, detectable levels of AGRP-like activity were reported in the lower picogram range. The serum AGRP levels were elevated in obese humans compared to lean controls and increased with fasting in rats.

Stem cell factor / KIT ligand (SCF) is a cytokine which binds CD117 (c-Kit). SCF is also known as "steel factor" or "c-kit ligand". SCF exists in two forms, cell surface bound SCF and soluble (or free) SCF. Soluble SCF is produced by the cleavage of surface bound SCF by metalloproteases.
SCF is a growth factor important for the survival, proliferation, and differentiation of hematopoietic stem cells and other hematopoietic progenitor cells. One of its roles is to change the BFU-E (burst-forming unit-erythroid) cells, which are the earliest erythrocyte precursors in the erythrocytic series, into the CFU-E (colony-forming unit-erythroid).

Human IL-36a belongs to the IL-1 family which includes IL-1b, IL-1a, IL-1ra, IL-18, IL-36ra (IL1F5), IL-36b (IL1F8), IL-36g (IL1F9), IL-37 (IL1F7) and IL-38 (IL-1F10). The IL-1 family members display a 12 b-strand, b-trefoil configuration, and are thought to have ascended from a mutual ancestral gene. IL-36a is an 18-22kDa, 158aa intracellular and secreted protein which holds no signal sequence, no prosegment and no potential from N-linked glycosylation sites. IL-36a is released as a reaction to LPS and the cell ATP-induced activation of the P2X7 receptor.
Human IL-36a (aa 6-158) shares 57-68% aa sequence homology with mouse, rabbit, equine and bovine IL-36a and 27-57% aa sequence homology with other new IL-1 family members. IL-36a is mostly found in skin and lymphoid tissues, but also in fetal brain, trachea, stomach and intestine.

Granulocyte/Macrophage Colony-Stimulating Factors are cytokines that act in hematopoiesis by controlling the production, differentiation, and function of 2 related white cell populations of the blood, the granulocytes and the monocytes-macrophages. MCSF induces cells of the monocyte/macrophage lineage. MCSF plays a role in immunological defenses, bone metabolism, lipoproteins clearance, fertility and pregnancy.

Osteoprotegerin, which is a member of the tumor necrosis factor receptor superfamily and is involved in the regulation of bone metabolism. OPGand its ligand (OPGL) are cytokines regulating osteoclasto-genesis. OPGL binds to receptors on the surface of preosteoclasts and stimulates their differentiation into active osteoclasts. This leads to osteoresorption. OPG inhibits this osteoclasto-genesis (OPG is secreted by osteoblasts, and binds to OPGL, thus inhibiting maturation of osteoclasts and osteoresorption). The degree and activity of osteoresorption depend mainly on the balance between OPG and its ligand (OPGL); factors increasing OPGL expression mostly reduce OPG expression and vice versa.

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, tumorigenesis and 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.

Troponin I, (TNNI1) is a member of the troponin I family. Troponin complex has 3 subunits, TNNI1 known as the inhibitory Subunit which prevents the actin-myosin interactions and thus mediating striated muscle relaxation. TNNI1 combines with tropomyosin and regulates calcium sensitivity of striated muscles by structural modifications in actin-myosin complexes.

Ankyrin Repeat Family A2, also known as ANKRA2 contains 5 ANK repeats. ANKRA2 assist endocytosis by linking megalin to components of the cytoskeleton or endocytic machinery.

The B7 proteins are crucial in the regulation of the adaptive immune system. Among them is NCR3LG1. NCR3LG1 is part of the B7 family and is expressed on tumor cells. NCR3LG1 Interaction with NKp30 protein results in cytotoxicity and natural killer cell activation.Humans and rats have a single NCR3LG1 gene; though, numerous B7H6 genes were detected in a single large cluster in the Xenopus genome. NCR3LG1, a ligand for the NK cell activating receptor NKp30, targest to produce CAR that targets multiple tumor types. NCR3LG1 is expressed on many primary human tumors, including leukemia, lymphoma and gastrointestinal stromal tumors, though it is not constitutively expressed on normal tissues.

Immediate Early Response 3 (IER3) functions in the protection of cells from Fas- or tumor necrosis factor type alpha-induced apoptosis. IER3 has a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK by phosphatase PP2A-PPP2R5C holoenzyme. In addition, IER3 serves as an ERK downstream effector mediating survival. As a member of the NUPR1/RELB/IER3 survival pathway, IER3 provides pancreatic ductal adenocarcinoma with significant resistance to cell stress, such as starvation.