Search results

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.

RANKL binds to tnfrsf11b/opg and to tnfrsf11a/rank. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive t-cell proliferation. May be an important regulator of interactions between t-cells and dendritic cells and may play a role in the regulation of the t-cell-dependent immune response. sRANKL may also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. By injecting soluble RANKL, novel osteopenia model mice were established in only 50 hours. Degree of bone loss can be controlled by changing doses of sRANKL. RANKL can be used in establishing osteopenia model for in vivo screening of drugs for osteoporosis, determination of effect and mechanism, evaluation of bone anabolic drugs.

ADP-ribosylation factor-like protein 9 (ARL9) is a member of to 2 novel subfamilies coding for small GTPases that were found to be highly conserved among eukaryotes.

Bcl2 modifying factor, is a member of the Bcl2 protein family of apoptosis mediators. Bcl2 modifying factor is widely expressed in many tissues.
Bcl2 modifying factor contains a single Bcl2 homology domain 3 (BH3), and binds Bcl2 proteins and functions as an apoptotic activator. Also, Bcl2 modifying factor is important for histone deacetylase (HDAC) inhibitors which alters the balance between acetylation and deacetylation, significantly increasing histone acetylation, while strongly inducing apoptosis in a variety of cancer cell types. Bcl2 modifying factor supports Bim in regulating cell death processes in response to many stimuli. A synergistic role for bim and Bcl2 modifying factor in an apoptotic pathway leading to the clearance of Neisseria gonorrhoeae -infected cells.

HB-EGF is an EGF related growth factor which signals via the EGF receptor, and stimulates the proliferation of SMC (smooth muscle cells), fibroblasts, epithelial cells and keratinocytes. HB-EGF is expressed in various cell types and tissues, including vascular endothelial cells and SMC, macrophages, skeletal muscle, keratinocytes and particular tumor cells. HB-EGF’s ability to explicitly bind heparin and heparin sulfate proteoglycans is dissimilar from other EGF-like molecules, and might be related to the enhanced mitogenic activity, relative to EGF, that HB-EGF exerts on smooth muscle cells.

Mimitin (NDUFAF2) is a member of the complex I NDUFA12 subunit family.NADH dehydrogenase is an enzyme located in the inner mitochondrial membrane, which catalyzes the transfer of electrons from NADH to coenzyme Q (CoQ). NDUFAF2 is the "entry enzyme" of oxidative phosphorylation in the mitochondria. Mimitin protein functions as a molecular chaperone for mitochondrial complex I assembly.

CFI cleaves and inactivates C3b and C4b. CFI is inactive without a cofactor such as the soluble factor H and C4b binding protein. CFI cleaves the alpha-peptide chain of C3b and C4b when these binds1 of the cofactors. This cleavage inactivates all of the complement activating functions of these proteins producing iC3b and iC4b.CFI cleaves the alpha chain of C3b twice and this releases a small fragment called C3f. CFI can cleave iC3b releasing C3c from C3dg in the presence of CR1.C4b is cleaved rapidly at 2 sites separating C4c from C4d.

The term ‘PDGF’ refers to a family of disulphide bond-linked dimeric isoforms that act as autocrine and paracrine growth factors and are produced by a variety of cell types other than platelets.
They act as potent mitogens for almost all mesenchymally-derived cells. Aberrant expression is involved in certain cancers, fibroproliferative disorders and atherosclerosis. The protein also contributes to wound healing and neural regeneration. There are four members of the PDGF family – PDGF A, PDGF B, PDGF C and PDGF D. Two distinct types of PDGF-A exist – a short form that is soluble and a long form that is retained by the extracellular matrix.

Fibroblast growth factor 16 (FGF16) is a member of the large FGF family, whose members are heparin-binding growth factors with a core 120 amino acid (a.a.) FGF domain which allows for a common tertiary structure. Human FGF16 cDNA is a 207 aa precursor protein with one N-linked glycosylation site. FGF16 though lacking a typical signal peptide, is efficiently produced by mechanisms other than the classical protein secretion pathway. FGF16 is expressed in cardiac cells and is required for proper heart development. FGF16 gene mutation was also observed in individuals with metacarpal 4-5 fusion. FGF16 has an imperative role in the regulation of embryonic development, cell proliferation and cell differentiation, and is required for normal cardiomyocyte proliferation and heart development.

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.

GMCSF is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of GMCSF is found extracellularly as a homodimer. GMCSF has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13.
GM-CSF stimulates the growth and differentiation of hematopoietic precursor cells from various lineages, including granulocytes, macrophages, eosinophils and erythrocytes.

ADP-Ribosylation Factor Interacting Protein 1 (ARFIP1) contains 1 AH domain and is a putative target protein of ADP-ribosylation factor.

Platelet-activating factor acetylhydrolase 2 cytoplasmic (PAFAH2) has a marked selectivity for phospholipids with short acyl chains at the sn-2 position. PAFAH2 may share a mutual physiologic function with the plasma-type enzyme.

General Transcription Factor IIA, 1 (GTF2A1) in a complex along with TBP mediates transcriptional activity. GTF2A1 is a part of the transcription machinery of RNA polymerase II and is also participates in transcriptional activation.

ARL3 (ARFL3) belongs to the ARF-like protein (ARL) subfamily of small GTPases. ARL3 does not activate the cholera toxin ADP-ribosyltranferase contrasting from ARFs. ARL3 is ubiquitously expressed. ARL3 may have a role in maintaining rod photoreceptor cells and regulating microtubule-dependent processes. ARL3 knockdown leads to altered cell morphology, failure of cytokinesis, acetylation of alpha tubulin and an increase in binucleated cells.

NGF-beta has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy, type 5 (HSAN5), and dysregulation of this gene's expression is associated with allergic rhinitis. Nerve Growth Factor was the 1st protein found from the family of neurotrophic factors that influence the growth and differentiation of sympathetic and sensory neurons. NGF consists of 3 different subunits: alpha, beta, and gamma. The beta subunit is accountable for its growth stimulating activity. The synthesis of NGF in astrocytes is enhanced by a range of cytokines such as IL1, TNF-a, PDGF & TGF-b.

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. Three main somatomedins have been characterized: somatomedin C (IGF1), somatomedin A (IGF2), and somatomedin B.

TRAF2 protein is related with transduce signals from members of the TNFR superfamily. TRAF2 is located in the cytoplasm binds to TRAF1, TRAF2, or TRAF3, thus inhibiting TRAF function by sequestering the TRAFs in a suppressed state in the cytoplasm. Overexpression of TANK inhibits TRAF2-mediated NF-Kappa-B activation signaled by CD40 and both TNF receptors and inhibits LMP1-mediated NF-kappa-B activation by blocking the association of TRAF2 with LMP1. TRAF2 is necessary for the cellular response to TNF-alpha by connecting upstream signalling molecules to the IKKs and p65.

The FGFs are a family of more than 20 small (~17–26 kDa) secreted peptides. The initial characterization of these proteins focused on their ability to stimulate fibroblast proliferation. This mitogenic activity was mediated through FGF receptors (FGFRs) 1, 2, or 3. A fourth closely related tyrosine kinase receptor (FGFR4) was able to bind the FGFs but did not lead to a mitogenic response.
FGFs modulate cellular activity via at least 5 distinct subfamilies of high-affinity FGF receptors (FGFRs): FGFR-1, -2, -3, and -4, all with intrinsic tyrosine kinase activity and, except for FGFR-4, multiple splice isoforms, and FGFR-5, which lacks an intracellular kinase domain. There is growing evidence that FGFRs can be important for regulation of glucose and lipid homeostasis. The overexpression of a dominant negative form of FGFR-1 in ? cells leads to diabetes in mice, which thus implies that proper FGF signaling is required for normal ? cell function and glycemia maintenance. FGFR-2 appears to be a key molecule during pancreatic development. Moreover, FGFR-4 has been implicated in cholesterol metabolism and bile acid synthesis.
FGF-19, has been shown to cause resistance to diet-induced obesity and insulin desensitization and to improve insulin, glucose, and lipid profiles in diabetic rodents. Since these effects, at least in part, are mediated through the observed changes in metabolic rates, FGF-19 can be considered as a regulator of energy expenditure.
FGF-21 is preferentially expressed in liver, but an exact knowledge of FGF-21 bioactivity and its mode of action have been lacking to date. FGF-21 is a potent activator of glucose uptake on adipocytes, protects animals from diet-induced obesity when overexpressed in transgenic mice, and lowers blood glucose and triglyceride levels when therapeutically administered to diabetic rodents.

GCSF is a cytokine that controls the production, differentiation, and function of granulocytes. The active protein is found extracellularly. 3 transcript variants encoding 3 different isoforms have been found for the GCSF gene. Granulocyte/macrophage colony-stimulating factors are cytokines that take part in hematopoiesis by controlling the production, differentiation, and function of 2 related white cell populations of the blood, the granulocytes and the monocytes-macrophages. This csf induces granulocytes.

Complement Factor Properdin (CFP) which is a plasma glycoprotein, is a positive regulator of the alternative complement pathway of the innate immune system. CFP binds and stabilizes the C3- and C5-convertase enzyme complexes in a feedback loop that eventually ends with formation of the membrane attack complex and lysis of the target cell. Mutations in CFP lead to 2 forms of properdin deficiency that cause high susceptibility to meningococcal infections.

TNF-related apoptosis-inducing ligand (TRAIL) is a ligand molecule which induces apoptosis. It is a type II transmembrane protein with homology to other members of the tumor necrosis factor family.
In humans, the gene that encodes for TRAIL is located at chromosome 3q26.
TRAIL binds to the death receptors, DR4 and DR5. The process of apoptosis is caspase-8-dependent. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues.

Acidic 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 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.