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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 modules: Module 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.

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.

GSTK1 is involved in cellular detoxification. GSTK1 is localized to the peroxisome and catalyzes the conjugation of the thiol group of glutathione (GSH) to the electrophilic groups of a broad range of hydrophobic substrates, leading to an easier removal of the latter from the cells.

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 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 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.

Mortality factor 4-like protein 1 (MORF4L1) is a member of the MRG family. MORF4L1 is a component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes mostly by acetylation of nucleosomal histones H4 and H2A. MORF4L1 is a transcription factor expressed in various human tissues, and its orthologs have been found in many other eukaryotes which comprise the MRG protein family. The C-terminal part of MORF4L1 forms a conserved MRG domain that is involved in interactions with the tumor suppressor protein retinoblastoma and a nucleoprotein.

GMFG is a hematopoietic-specific protein that mediates the pluripotentiality and lineage commitment of human hematopoietic stem cells. Glia maturation factor gamma is a cytokine-responsive protein in EPO-induced and G-CSF-induced hematopoietic lineage development. Glia maturation factor also acts as a Nerve Growth Factor in nervous system development, angiogenesis and immune function. GMFG possesses hematopoietic tissue-specific gene expression, a promoter concentrated with high-score hematopoiesis-specific transcription factors, and molecular coevolution with a rudimentary blood/immune system.

TGFBI is an extracellular matrix protein induced by transforming growth factor (TGF)-beta 1. TGFBI protein is involved in cell growth, cell differentiation, wound healing and cell adhesion. In addition, some missense mutations of TGFBI were identified in families affected with human autosomal dominant corneal dystrophies. TGFBI gene encodes for a 683 amino-acid protein containing an RGD motif and four internal repeated domains which have highly conserved sequences founded in several species (Fasciclin domain).

Glia Maturation Factor-Beta (GMF-Beta) is a 17 kDa protein nerve gorwth factor identified as a growth and differentiation factor in the vertebrate brain.
Glia Maturation Factor-Beta stimulates differentiation of normal neurons as well as glial cells. GMFB inhibits the proliferation of the N-18 neuroblastoma line and the C6 glioma line while promoting their phenotypic expression.
GMF-beta inhances the phenotypic expression of glia & neurons thus inhibits the proliferation of their respective tumors when added to cell culture. Although astrocytes produce GMF-b and stores it inside the cells, they don’t secrete the GMF-B into the cultured medium. Cell- surface GMFb acts on the target cells at close range when cells are in direct contact. GMF-Beta is produced by thymic epithelial cells and plays an important role in T cell development in favor of CD4+ T cells.
GMF-Beta is a brain-specific protein which belongs to the actin-binding proteins (ADF) family. GMF-beta appears to play a role in the differentiation, maintenance, and regeneration of the nervous system. It also supports the progression of certain auto-immune diseases, possibly through its ability to induce the production and secretion of various pro-inflammatory cytokines.

NFATC1 is a component of the nuclear factor of activated T cells DNA-binding transcription complex. This complex consists of at least 2 components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation, and an inducible nuclear component. Proteins belonging to this family of transcription factors play an essential role in inducible gene transcription during immune response. NFATC1 is an inducible nuclear component. NFATC1 functions as a major molecular target for the immunosuppressive drugs such as cyclosporin A. Different isoforms of NFATC1 may regulate inducible expression of different cytokine genes.

TGFB2 is a 27.08 kDa protein having two identical 118 amino acid peptide chains linked by a single disulfide bond. TGFB2 is part of a family of five related cytokines that have an extensive variation of normal and neoplastic cells, indicating the importance of these homo-dimmer proteins as multi-functional regulators of cellular activity. The three mammalian isoforms of TGF-beta (TGFb1, TGFb2 and TGFb3) signal through the same receptor and stimulate similar biological responses. They are involved in physiological processes as embryogenesis, tissue remodelling and wound healing.

GDF-5 is a member of the bone morphogenetic protein (BMP) family and the TGF-beta superfamily. This group of proteins is characterized by a polybasic proteolytic processing site which is cleaved to produce a mature protein containing seven conserved cysteine residues. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Mutations in this gene are associated with acromesomelic dysplasia, Hunter-Thompson type; brachydactyly, type C; and chondrodysplasia, Grebe type. These associations confirm that the gene product plays a role in skeletal development.

Cytosolic and membrane-bound types of GST are encoded by 2 different supergene families. There are 8 classes of the soluble cytoplasmic mammalian GST: alpha, kappa, mu, omega, pi, sigma, theta and zeta. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are arranged in a gene cluster on chromosome 1p13.3 and aare highly polymorphic. These genetic differences can change an individual's resistance to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Null mutations of this class mu gene have been linked with the rise in a number of cancers.

TGF-beta receptor-associated protein 1 also known as TGFBRAP1 takes part in the TGF-beta/activin signaling pathway. TGFBRAP1 is related with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling. TGFBRAP1recruits SMAD4 to the vicinity of the receptor complex and smoothes the progress of its interaction with receptor-regulated Smads, such as SMAD2.

GDNF promotes the survival and differentiation of neurons in culture, and is able to prevent apoptosis of motor neurons induced by axotomy. The encoded protein is processed to a mature secreted form that exists as a homodimer. The mature form of the protein is a ligand for the product of the RET (rearranged during transfection) protooncogene. In addition to the transcript encoding GDNF, two additional alternative transcripts encoding distinct proteins, referred to as astrocyte-derived trophic factors, have also been described. Mutations in this gene may be associated with Hirschsprung disease.
GDNF enhances survival and morphological differentiation of neurons and increases their high-affinity uptake.

PDGF-AA, PDGF-BB and PDGF-AB, are potent mitogens for a variety of cell types including smooth muscle cells, connective tissue cells, bone and cartilage cells, and some blood cells. The PDGF is stored in platelet alpha-granules and released upon platelet activation. The PDGF is involved in a number of biological processes, including hyperplasia, chemotaxis, embryonic neuron development, and respiratory tubule epithelial cell development. Two distinct signaling receptors used by PDGF have been identified and named PDGFR-alpha and PDGFR-beta. PDGFR-alpha is high-affinity receptor for each of the three PDGF forms. On the other hand, PDGFR-beta interacts with only PDGF-BB and PDGF-AB.

Proteins of the TFF family are characterized by obtaining a minimum of 1 copy of the trefoil motif, a 40-amino acid domain that contains 3 conserved disulfides. Trefoil Factors are stable secretory proteins expressed in gastrointestinal mucosa which protect the mucosa from insults, stabilize the mucus layer and affect healing of the epithelium.TFF2 inhibits gastric acid motility & secretion. TFF2 stabilizes glycoproteins in the mucus gel through interactions with carbohydrate side chains. TFF3 induces ciliogenesis and promotes airway epithelial ciliated cell differentiation, relatively through an epidermal growth factor receptor-dependent pathway. TFF3 overexpression is crucial for progression in mouse and human hepatocellular carcinogenesis. TFF-3 is normally expressed in hepatocellular carcinoma and its expression associates with tumor grade.

TGFBR2 is part of the Ser/Thr protein kinase family and the TGFB receptor subfamily. TGFBR2 is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with another receptor protein, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of a subset of genes related to cell proliferation. Mutations in TGFBR2 gene have been associated with Marfan syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. TGFBR2 expression is increased in oral squamous cell carcinoma cells. TGFBR2 attenuates the biological activities of TGF-beta in colorectal cancer. TGFBR2 expression is decreased by IL-1beta while inducing Sp3 via NFkappaB. TGFB2 and TGFBR2 are involved in the antiestrogenic activity of tamoxifen metabolites in breast cancer.

Growth Differentiation Factor-7 (GDF-7) belongs to the BMP family of TGF-b superfamily proteins. GDF7 elicits its bioactivity via a heterodimeric receptor complex comprised of a type 1 (BMPR-IB) and a type II (BMPR-II or Activin RII) serine/threonine kinase receptor. GDF7 signaling results in the phosphorylation and activation of Smad proteins. GDF-7 is also involved in tendon and ligament formation and repair. In addition, GDF7 regulates bone formation, mesenchymal stem cell differentiation, neuronal differentiation, and axon guidance.

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.

Leucine Zipper Transcription Factor-Like 1, also known as LZTFL1 is a ubiquitously expressed protein which localizes to the cytoplasm. LZTFL1 interacts with Bardet-Biedl Syndrome proteins (BBS) and during its interaction with BBS protein complexes, regulates protein trafficking to the ciliary membrane. Nonsense mutations in LZTFL1 cause a form of Bardet-Biedl Syndrome; a ciliopathy characterized partly by polydactyly, obesity, cognitive impairment, hypogonadism, and kidney failure. LZTFL1 also acts as a tumor suppressor; possibly by interacting with E-cadherin as well as the actin cytoskeleton and in this manner regulating the transition of epithelial cells to mesenchymal cells.

FGF8 is part of the fibroblast growth factor family. FGF family members have wide mitogenic and cell survival activities, and participate in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. FGF8 supports androgen and anchorage independent growth of mammary tumor cells. FGF8 over expression increases tumor growth and angiogensis. The adult expression of FGF-8 gene is restricted to testes and ovaries. FGF8 functions as an embryonic epithelial factor. FGF8 takes part in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination.

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.