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CST4 is a member of the cystatin superfamily which contains proteins that hold multiple cystatin-like sequences. Several family members are active cysteine protease inhibitors, whereas others have lost or possibly never attained this inhibitory activity. CST4 strongly inhibits papain (non-competitively) and ficin, partially inhibits stem bromelain and bovine cathepsin C, however does not inhibit porcine cathepsin B or clostripain.

PLGF is a growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration. It binds to receptor vegfr-1/flt1.
PLGF-2 binds neuropilin-1 and 2 in a dependent manner.

TNFR1 belongs to the TNF-receptor superfamily. TNFR1 is a receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha.
There are 2 types of soluble TNF receptors: sTNFR-I and sTNFR-II, which act to neutralize the biological activities of TNF alpha and TNF beta. The levels of these soluble receptors seem to increase as a result of shedding of the extracellular domains of the membrane bound receptors. TNF-a, TNFR1 and TNFR2 have roles in cellular differentiation. TNFR1 and TNFR2 function in cell type-specific renal injury.
TNFR1 is capable of signaling both cell survival and apoptosis. TNFR1-induced apoptosis requires 2 sequential signaling complexes. TNFR1 is capable of activating NF-kappaB, mediate apoptosis, and function as a regulator of inflammation. Oxidative stress promotes TNFR1 and TNFR2 self-interaction, ligand-independent and enhanced ligand-dependent TNF signaling. TNFR1 contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase. Human TNFR1 has a major region which controls cell surface expression. High levels of soluble TNF receptors are found in the amniotic fluid of pregnant women.
Germline mutations of the extracellular domains of TNFR1 are linked to the autosomal dominant periodic fever syndrome. The impaired receptor clearance is believed to be a mechanism of the disease. Familial hibernian fever (FHF) is caused by defects in TNFRSF1A gene.

Potassium Channel Tetramerisation Domain Containing 11 (KCTD11) is a 232 amino acid regulator of neuronal differentiation which induces growth arrest, apoptosis and the expression of p27 (cyclin-dependent kinase inhibitor). KCTD11 is expressed most highly in cerebellum. KCTD11 functions as an antagonist of the Hedgehog pathway and activator of the caspase cascade and among its related super-pathways are Melatonin Signaling and Activation of cAMP-Dependent PKA.

Vascular endothelial growth factor is an important signaling protein involved in both angiogenesis and vasculogenesis.VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g. stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells ).VEGF mediates increased vascular permeability, induces angiogenesis, vasculogenesis and endothelial cell growth, promotes cell migration, and inhibits apoptosis. In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.
Elevated levels of VEGF is linked to POEMS syndrome, also known as Crow-Fukase syndrome. Mutations in VEGF have been associated with proliferative and nonproliferative diabetic retinopathy.

40S ribosomal protein S13 (RPS13), is a member of the ribosomal protein S15P family. Ribosomes are the organelles which catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. RPS13 is located in the cytoplasm and contains multiple phosphorylated residues. Similar to other ribosomal proteins, Ribosomal Protein S13 exists as multiple processed pseudogenes which are scattered throughout the genome.

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.

CD74 (HLA class II histocompatibility antigen gamma chain isoform b), is a transmembrane protein (on antigen presenting cells) which is the invariant chain that chaperones MHC class IIdimers from the endoplasmic reticulum to the cell surface. CD74 is expressed by cells of both T lymphocyte and Blymphocyte lineages. CD74 upregulated in several cancers and is also expressed by non immune cells during inflammation. Diseases related with CD74 include thymic epithelial neoplasm and gastroduodenitis. Among its related super-pathways are Immune System and Immune response Antigen presentation by MHC class II. In addition CD74 functions as cell surface receptor for the cytokine MIF.

The acute phase plasma protein ORM1 synthesized by the liver mediates the interaction between blood cells and endothelial cells. In addition, together with haptoglobin and C reactive protein, ORM1 regulates the extravasation of the cells through infection and inflammation. Expression of ORM1 is induced by acute-phase stimulatory mediators such as bacterial lipopolysaccharides.

Ubiquitin is a highly conserved 76 amino acid protein expressed in all eukariotes. Ub is found either in free form or conjugated to proteins as monomer or as chain of ubiquitin molecules. The most well characterized consequence of polyubiquitination is substrate degradation, while mono-ubiquitinated proteins are not degraded. Ubiquitin attachment to protein substrate is a complex process involving a ubiquitin activating enzyme (E1), a ubiquitin conjugating enzyme (E2) and a ubiquitin protein ligase (E3). The first ubiquitin moiety is transferred to the e-NH2 group of a Lys residue of the protein substrate to generate an isopeptide bond. In successive reactions, a poly ubiquitin chain is synthesized by processive transfer of additional activated moieties to Lys48 of the previously conjugated ubiquitin molecule. Ubiquitin K48R prevents the formation of poly ubiquitin chains via Lys48 linkages with mono ubiquitin molecules, avoiding the degradation of protein substrates.

Granzyme H also known as GZMH belongs to the peptidase S1 family. GZMH is an essential part for HBV eradication. The HBx protein, which is required for the replication of HBV, is cleaved at Met(79) by GZMH. Furthermore, GZMH inhibitor can abolish GZNH- as well as lymphokine-activated killer cell-mediated HBx degradation and HBV clearance. A HBx-deficient HBV is resistant to GzmH- in addition to lymphokine-activated killer cell-mediated viral clearance.

Basic fibroblast growth factor is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein functions as a modifier of endothelial cell migration and proliferation, as well as an angiogenic factor. It acts as a mitogen for a variety of mesoderm- and neuroectoderm-derived cells in vitro, thus is thought to be involved in organogenesis. Three alternatively spliced variants encoding different isoforms have been described. The heparin-binding growth factors are angiogenic agents in vivo and are potent mitogens for a variety of cell types in vitro. There are differences in the tissue distribution and concentration of these 2 growth factors.

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.

Myozenin 1 (MYOZ1) is a member of the myozenin family. MYOZ1 is mostly expressed in the skeletal muscle. Members of the myozenin family act as calcineurin-interacting proteins which helps tether calcineurin to the sarcomere of cardiac and skeletal muscle. The myozenin family plays a significant role in modulation of calcineurin signaling.

The clinical use of the potent anti-tumor activity of TNF-a has been limited by the proinflammatory side effects including fever, dose-limiting hypotension, hepatotoxicity, intravascular thrombosis, and hemorrhage. Designing clinically applicable TNF-a mutants with low systemic toxicity has been an intense pharmacological interest. Human TNF-a, which binds to the murine TNF-R55 but not to the mouse TNF-R75, exhibits retained anti-tumor activity and reduced systemic toxicity in mice compared with murine TNF-a, which binds to both murine TNF receptors. Based on these results, many TNF-? mutants that selectively bind to TNF-R55 have been designed. These mutants displayed cytotoxic activities on tumor cell lines in vitro, and exhibited lower systemic toxicity in vivo.
Recombinant Human TNF-a Variant/Mutant compared with the wild-type, has an amino acid sequence deletion from a.a. 1-7, and the following a.a. substitutes Arg8, Lys9, Arg10 and Phe157 which is proven tohave more activity and with less inflammatory side effect in vivo.

The somatomedins, or IGFs, comprise a family of peptides that play important roles in mammalian growth and development. IGF1 mediates many of the growth-promoting effects of GH. Early studies showed that GH did not directly stimulate the incorporation of sulfate into cartilage, but rather acted through a serum factor, termed 'sulfation factor,' which later became known as 'somatomedin' (Daughaday et al., 1972). Three main somatomedins have been characterized: somatomedin C (IGF1), somatomedin A (IGF2; MIM 147470), and somatomedin B (MIM 193190) (Rotwein, 1986; Rosenfeld, 2003).

Chemokine (C-X-C motif) ligand 10 (CXCL10) is a small cytokine belonging to the CXC chemokine family that is also known as 10 kDa IP-10. CXCL10 is secreted by several cell types in response to IFN-?. These cell types include monocytes, endothelial cells and fibroblasts. CXCL10 has been attributed to several roles, such as chemoattraction for monocytes and T cells, promotion of T cell adhesion to endothelial cells, antitumor activity, and inhibition of bone marrow colony formation and angiogenesis. The gene for CXCL10 is located on human chromosome 4 in a cluster among several other CXC chemokines. This chemokine elicits its effects by binding to the cell surface chemokine receptor CXCR3. The three-dimensional crystal structure of this chemokine has been determined under 3 different conditions to a resolution of up to 1.92A.

Osteoprotegerin acts as decoy receptor for rankl and thereby neutralizes its function in osteoclastogenesis. OPG inhibits the activation of osteoclasts and promotes osteoclast apoptosis in vitro. Bone homeostasis seems to depend on the local rankl/opg ratio. Osteoprotegerin may also play a role in preventing arterial calcification. May act as decoy receptor for trail and protect against apoptosis. Trail binding blocks the inhibition of osteoclastogenesis.

RLBP1 is a 36-kD water-soluble protein that transports 11-cis-retinal or 11-cis-retinaldehyde as physiologic ligands. RLBP1 is a functional element of the visual cycle. RLBP1 gene mutations cause retinitis punctata albescens, severe rod-cone dystrophy and Bothnia dystrophy (nonsyndromic autosomal recessive retinitis pigmentosa).

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.

GAP43 is a phosphoprotein of the presynaptic membrane that takes part in synaptic reorganization and neural development. GAP43 is found in large quantities in neuronal growth cones all through the development and axonal regeneration. Additionally, GAP43 is involved in specific regions of the normal adult nervous system and has a vital part in the conservation mechanism of long-term potentiation (LTP).

Neuregulin/Heregulin is a family of structurally related polypeptide growth factors which are stemmed from alternatively spliced genes (NRG1, NRG2, NRG3 and NRG4). There are more than 14 soluble and transmembrane proteins derived from the NRG1 gene. Proteolytic processing of the extracellular domain of the transmembrane NRG1 isoforms release soluble growth factors. These isoforms contain the heregulins (HRGs), glial growth factors (GGFs) and sensory and motor neuron-derived factor (SMDF). All these factors have the Ig and EGF-like domain, and are able to bind to ErbB3 and ErbB4 receptor tyrosin kinases. This binding stimulates erb3 and erb4 heterodimerization with erb2, promoting intrinsic kinase activity, which results in tyrosine phosphorylation. NRG1 isoforms induce the growth and differentiation of epithelial, neuronal, glial, and other types of cells.