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Furin is a member of the peptidase S8 family. Furin signifies the ubiquitous endoprotease activity within constitutive secretory pathwaysas well as capable of cleavage at the RX (K/R) R consensus motif.Furin is considered to be one of the proteases responsible for the activation of HIV envelope glycoproteins gp160 as well as gp140 and might take part in tumor progression. Among the diseases associated with FURIN are dementia, familial british and plague.

GADD45G is part of the nuclear proteins to interact with various proteins whose transcript levels are raised after stressful growth arrest conditions and treatment with DNA-damaging agents. GADD45G reacts to environmental stresses by mediating activation of the p38/JNK pathway which is mediated through their protein binding and activating MTK1/MEKK4 kinase, which is an upstream activator of both p38 and JNK MAPKs. GADD45G acts as a new-age tumor suppressor however is being frequently inactivated epigenetically in multiple tumors. GADD45G mRNA expression is down-regulated in hepatocellular carcinoma. GADD45G causes cell cycle arrest at G2/M transition when transfected into Hep-G2 cells. GADD45 Gamma induction by androgens involves new protein synthesis. Overexpression of GADD45 Gamma inhibits cell growth and causes morphological modifications in prostate cell lines thus GADD45 gamma takes part in differentiation induction by androgens.

Glycerol dehydrogenase (GldA) catalyzes the NAD-dependent oxidation of glycerol to dihydroxyacetone (glycerone). The GldA protein allows microorganisms to use glycerol as a source of carbon under anaerobic conditions. Furthermore, in E.coli GldA has an imperative role by regulating the intracellular level of dihydroxyacetone by catalyzing the reverse reaction, i.e. the conversion of dihydroxyacetone into glycerol. GldA possesses an extensive substrate specificity, due to its ability to oxidize 1,2-propanediol and to reduce glycolaldehyde, methylglyoxal and hydroxyacetone into ethylene glycol, lactaldehyde and 1,2-propanediol, respectively.

Protease Serine 7, also known as PRSS7, is in charge of initiating the activation of pancreatic proteolytic proenzymes such as trypsin, chymotrypsin and carboxypeptidase A. PRSS7 catalyzes the conversion of trypsinogen to trypsin which in turn activates other proenzymes including chymotrypsinogen, procarboxypeptidases, as well as proelastases.

UCK1 is a uridine-cytidine kinase which catalyzes the phosphorylation of uridine and cytidine to uridine monophosphate and cytidine monophosphate. UCK1 does not phosphorylate deoxyribonucleosides or purine ribonucleosides. UCK1 is also phosphorylates uridine and cytidine analogs and uses ATP and GTP as a phosphate donor.

Prefoldin subunit 3 (VBP1) is a member of the prefoldin subunit alpha family. VBP1 interacts with the Von Hippel-Lindau protein in order to create an intracellular complex. Since VBP1 serves as a chaperone protein, it is assumed to have a role in the transport of the Von Hippel-Lindau protein from the perinuclear granules to the nucleus or cytoplasm. VBP1 binds specifically to cytosolic chaperonin (c-CPN) and transfers target proteins to it. VBP1 also binds to nascent polypeptide chain and stimulates folding in an environment in which there are numerous competing pathways for nonnative proteins.

XIAP Associated Factor 1 (XAF1) is a protein which binds to and counteracts the inhibitory effect of a member of the IAP (inhibitor of apoptosis) protein family. IAP proteins bind to and inhibit caspases which are activated in the course of apoptosis. The ratio of IAPs and proteins which interfere with their activity, such as the XAF1 protein, influence the progress of the apoptosis signaling pathway. Additionally, XAF1 inhibits anti-caspase activity of BIRC4. XAF1 induces cleavage and inactivation of BIRC4 independent of caspase activation. Furthermore, XAF1 mediates TNF-alpha-induced apoptosis and is involved in apoptosis in trophoblast cells.

REG protein was shown to be stimulated during the regeneration of pancreatic islets. Since then, many Reg-related proteins have been identified in humans and other animals. In human, the four REG family genes, i.e., REG 1 alpha, REG 1 beta, REG-related sequence (RS) and HIP/PAP, have so far been isolated. These Reg-related proteins are classified into four subfamilies according to their amino-acid sequences, but they share a similar structure and physiological function. Reg protein is a growth factor for pancreatic beta cells and also suggests that the administration of Reg protein could be used as another therapeutic approach for diabetes mellitus. Human REG cDNA which encodes a 166-amino acid protein with a 22-amino acid signal peptide. The amino acid sequence of human REG protein has 68% homology to that of rat Reg protein.
Reg I was found to be expressed mainly in pancreatic beta and acinoductular cells as well as gastric fundic enterochromaffin-like (ECL) cells. Reg I production in ECL cells is stimulated by gastrin, as well as by the proinflammatory cytokine, cytokine-induced neutrophil chemoattractant (CINC)-2Beta. In patients with chronic hypergastrinemia, Reg production is stimulated, with the increased proliferation of gastric mucosal cells. Patients with Helicobacter pylori infection also showed increased Reg production in the gastric mucosa, partly via increased plasma gastrin concentration and partly via increased proinflammatory cytokine production. The serum concentration of the reg-protein was significantly higher in patients with various pancreatic diseases than in normal controls, and was also significantly higher in patients with acute pancreatitis or chronic relapsing pancreatitis than in patients with chronic pancreatitis. Furthermore, the serum PSP/reg-protein concentration was also significantly increased in liver cirrhosis, choledocholithiasis, and various cancers of the digestive system.

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 HIMF stimulated 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.

Renin is a highly specific endopeptidase which generates angiotensin I from angiotensinogen in the plasma. angiotensin I is an important regulator of blood pressure and electrolyte balance. Renin initiates a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.

Cystatin 7 (CST7) is a glycosylated cysteine protease inhibitor with a putative role in immune regulation through inhibition of a unique target in the hematopoietic system. Cystatin-7 is comprised of multiple cystatin-like sequences. The superfamily is comprised of 3 inhibitory families: the type 1 cystatins (stefins), type 2 cystatins and the kininogens. Some members are active cysteine protease inhibitors, while others have lost or possibly never had this inhibitory activity. Type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in various human fluids and secretions. CST7 protein expression has been observed in numerous human cancer cell lines established from malignant tumors.

Cyclophilin-C belongs to the peptidyl-prolyl cis-trans isomerase (PPIase)) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. Like other PPIases, the Cyclophilin-C protein can bind immunosuppressant cyclosporin A.

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.

Alpha 1-microglobulin (A1M) is a lipocalin superfamily member (kernal lipocalins). A1M is a low molecular weight protein component of plasma. A1M is distributed in plasma and extravascular compartments of all organs. Alpha-1 Microglobulin is found in mammals, birds, amphibians and fish. The primary sites of A1M synthesis are the liver and the kidney. Around the opening of the lipocalin pocket three lysyl residues are situated; those residues carry yellow-brown modification derived from the binding and degradation of heme and kynurenin (a tryptophan metabolite). A1-Microglobulin’s reductase and dehydrogenase have broad biological substrate specificity properties due to its’ free cysteine side-chain which is located in a flexible loop. Alpha-1-microglobulin is glycosylated by three separate carbohydrate chains: two complex carbohydrates which are N-linked to asparagines at residues 17 and 96, and the other simple carbohydrate which is O-linked to threonine at position 5. The carbohydrates comprise 22% of the total molecular mass of the protein. The glycosylation varies between species.
A1M exists in two forms- a free form and complexed to other macromolecules: in humans- complexed to immunoglobulin A (IgA), in rat- complexed to alpha-1-inhibitor-3. Free A1M is exceptionally heterogeneous in charge (therefore also known as protein HC), and is found tightly linked to a chromophore. The free Alpha-1-microglobulin is a monomeric protein composed of one 188 residue polypeptide and contains three cysteines, two of which (residues 75 and 173) form a conserved intra-molecular disulphide link. The chromophoric group is covalently bound to the free cysteine residue at position 34. A1M binds retinol as a major ligand, but this is probably distinct from its covalent chromophore.
Half of all human plasma A1M (approximately 0.03mg/ml) forms a 1:1 complex with about 5% of plasma immunoglobulin A. The resulting macromolecular complexes’ molecular weight is 200000, and a plasma concentration of 0.3mg/ml. The complex can exhibit both antibody activity and affect many of the biological actions of free Alpha-1-microglobulin.
Alpha-1-microglobulin was first discovered in pathological human urine.
It was suggested that A1M might be involved in tissue defense against reactive oxygen species, oxidation by heme and kynurenin. Evidence also suggests that A1M functions in the regulation of the immune system. Other functions include inhibition of stimulation of cultured lymphocytes by protein antigens; induction of cell division of lymphocytes, a mitogenic effect that can either be enhanced or inhibited by the action of other plasma components; inhibition of neutrophil granulocyte migration in vitro; and inhibition of chemotaxis.

Myostatin (GDF-8), a member of the TGFbeta superfamily, is a potent and specific negative regulator of skeletal muscle mass. In serum, myostatin circulates as part of a latent complex containing myostatin propeptide and/or follistatin-related gene. The myostatin propeptide is known to bind and inhibit myostatin in vitro. This interaction is relevant in vivo, with a majority (>70%) of myostatin in serum bound to its propeptide. The myostatin propeptide is negative regulator of myostatin in vivo.

NFKB inhibitor interacting Ras-like 2 (NKIRAS2) is an inhibitor of the transcription factor NF-kappaB. NKIRAS2 is similar to the Ras-like small GTPases which associate with IkappaB. The Ras-like proteins- NKIRAS1 and NKIRAS2, interact with the PEST domains of I?B? and I?B? and reduce their rate of degradation. NKIRAS2 is an atypical Ras-like protein which functions as a potent regulator of NF-kappa-B activity by preventing the degradation of NF-kappa-B inhibitor beta (NFKBIB) by most signals, explaining why NFKBIB is more impervious to degradation.

Bcl-2–associated X protein (Bax) belongs to the Bcl-2 protein family. Bax is a pro-apoptotic Bcl-2 protein containing BH1, BH2 and BH3 domains. Bax accelerates programmed cell death by binding to, and antagonizing the apoptosis repressor bcl2 or its adenovirus homolog e1b 19k protein. Bax induces the release of cytochrome c, activation of casp3, and thereby apoptosis. Bax is expressed in a wide variety of tissues, with highest levels in the testis and ovary. Tumor suppressor protein p53 upregulates the expression of BAX. Bax has been shown to be involved in p53-mediated apoptosis.

Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6. This gene encodes a growth regulator which inhibits the proliferation of a number of tumor cell lines. It regulates cytokine production, including IL-6, G-CSF and GM-CSF from endothelial cells.

This gene is a member of the EPO/TPO family and encodes a secreted, glycosylated cytokine composed of four alpha helical bundles. The protein is found in the plasma and regulates red cell production by promoting erythroid differentiation and initiating hemoglobin synthesis. This protein also has neuroprotective activity against a variety of potential brain injuries and antiapoptotic functions in several tissue types.

Platelet Factor 4 Variant 1 (PF4V1) is a member of the intercrine alpha (chemokine CxC) family. PF4V1 is an inhibitor of angiogenesis and inhibitor of endothelial cell chemotaxis (in vitro).

The peroxisome proliferator activated receptors (PPARs) are ligandactivated transcription factors within the nuclear receptor superfamily, which play important roles in adipogenesis, glucose homeostasis andinflammation. Three different isotypes can be distinguished; alpha, beta and gamma. PPARg, is mainly expressed in adipose tissue and to lesser extent in colon, the immune system and the retina. Whereas PPARg operates in the catabolism of fatty acids in the liver, PPARg influences the storage of fatty acids in the adipose tissue and plays a role in adipocyte differentiation. PPARg binds to DNA as a heterodimer with retinoid X receptor (RXR), activating expression of target genes after binding ligand.

Heat-stable enterotoxins (STa) are small, cysteine-rich peptides secreted by Escherichia coli that are able to induce diarrhea through the stimulation of an intestine-specific receptor-guanylyl cyclase known as STaR. Binding of STa to STaR induces a dramatic increase in the cGMP content of the cell; the increase, in turn, inhibits salt absorption and stimulates chloride secretion. This imbalance of ions is accompanied by a massive accumulation of water in the gut that gives rise to the diarrhea and dehydration characteristic of enterotoxin activity. The identification of a receptor for STa on intestinal brush border membranes suggested the existence of an endogenous activator, described guanylin, a 15-amino acid peptide purified from rat small intestine, as a potential ligand for the STaR. This peptide shares sequence similarity with STa; see also uroguanylin. The molecular cloning of the human and mouse cDNAs encoding guanylin was reported. The sequences demonstrated that guanylin is present at the C-terminal end of a larger precursor protein. Expression in mammalian cells indicated that the 94- amino acid proguanylin is inactive. The biologically active guanylin can be released by either chemical or enzymatic treatment of proguanylin. By Northern blot analysis and in situ hybridization, showed that expression of guanylin mRNA is restricted to cells of the intestinal epithelium, specifically the Paneth cells at the base of the small intestinal crypts. These results demonstrate that guanylin is an endogenous activator of STaR isolated a cDNA encoding an apparent precursor of guanylin from a human intestinal cDNA library. The mRNA was expressed at high levels in human ileum and colon. In the mouse, interspecific backcross analysis used to map the Guca2 gene to the distal half of mouse chromosome 4 in a region of homology with human chromosome 1p. By fluorescence in situ hybridization mapped the GUCA2 gene to human 1p35-p34 Guanylin is thought to modulate intestinal water/electrolyte transport in a paracrine mode reported the nucleotide sequence of the gene, the characteristics of its circulating molecular form, and its localization in enterochromaffin cells of the gut. The gene, approximately 2.6 kb in size, consists of 3 exons interrupted by 2 introns. The hormonal form of guanylin is a 94-amino acid peptide with a molecular mass of 10.3 kDa. Guanylin is synthesized by gut enterochromaffin cells as a prohormone of 115 amino acids and is processed to the molecular form of 94 amino acids circulating in the blood.

Uromodulin is the most abundant protein in normal urine. Its secretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin plays a role as a constitutive inhibitor of calcium crystallization in renal fluids. Secretion of uromodulin in urine provides protection against urinary tract infections caused by uropathogenic bacteria. Defects in Uromodulin expression are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN). These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive renal failure. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. UMOD is involved in regulating the circulating activity of cytokines as it binds to il-1, il-2 and tnf with high affinity.