EGF (epidermal growth factor) is the founding member of the EGF family of proteins, which also include Amphiregulin (AREG), Betacellulin (BTC), Epiregulin (EPR), HB-EGF, Neuregulins, and others. Members of epidermal growth factor family have highly similar structural and functional characteristics. They have at least one common structural motif, the EGF domain, which consists of six conserved cysteine residues forming three disulfide bonds. The main structure of EGF domain is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet. In addition to their EGF domain, the epidermal growth factor family members are characterized by two features: Production of mitogenic responses in EGF-sensitive cells, and high affinity binding to the EGF receptor.
The activity of epidermal growth factor family members is mediated by the epidermal growth factor receptor tyrosine kinases (EGFR/ErbB). Members of the EGFR/ErbB family are made up of an extracellular region or ectodomain that contains approximately 620 amino acids, a single transmembrane spanning region and a cytoplasmic tyrosine kinase domain. The extracellular domain of the EGF receptor is characterized by its capacity to bind EGF and EGF-like ligands with high affinity. Chemically this portion of the receptor contains 10-11 N-linked oligosaccharide chains, high content of half-cystine residues (10%) that could give rise to as many as 25 disulfides. The region between the two half-cystine-rich clusters is involved in ligand binding. The hallmark of the cytoplasmic portion of epidermal growth factor receptor is the sequence defining the tyrosine kinase domain. Near the carboxyl terminus of the receptor are four sites of EGF-dependent autophosphorylation.Epidermal growth factor plays an important role in the regulation of cell growth, proliferation, and differentiation.
The transforming growth factor beta 1 (TGF-beta 1) is the first member of the TGF-beta superfamily that is comprised of a large group of proteins, including the activin/inhibin family, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs) and the TGF-beta subfamily. Members of the TGF-beta superfamily interact with a conserved family of cell surface serine/threonine-specific protein kinase receptors to activate Smad signaling cascades.
Another subfamily of the TGF-beta superfamily is GDNF (glial cell line-derived neurotrophic factor) family. The GDNF family ligands share a similar conformation with other members of the TGF-beta superfamily. However, proteins of the GDNF family do not signal through TGF-beta receptors. They signal through a multimolecular protein complex that includes the RET receptor tyrosine kinase and receptors of the GFR-alpha family.
TGF-beta superfamily of cytokines bind to receptors at the cell surface, and recruit two type I receptors and two type II receptors forming a tetrameric complex. Activated TGF-beta superfamily receptors induce a series of phosphorylation cascade, from receptor phosphorylation to subsequent phosphorylation and activation of downstream signal transducer R-Smads (receptor-activated Smads). Phosphorylated R-Smads form a heteroligomeric (often trimeric) complex with Smad4 (Co-Smad). The Smad complex is imported into the nucleus and regulates the expression of target genes by direct binding to the target gene promoter and/or through the interaction with transcriptional cofactors in a cell-type-specific manner. TGF-beta superfamily signaling controls numerous cellular responses from cell proliferation, differentiation and extracellular matrix remodelling to embryonic development in species ranging from worms to mammals.
Besides the canonical Smad-mediated TGF-beta signaling pathway, it has been shown that TGF-beta superfamily ligands can also regulate cellular or physiological processes through non-canonical pathways by the activation of other signaling molecules [e.g. Akt, MAPK (mitogen-activated protein kinase), mTOR (mammalian target of rapamycin), and Src] independent of Smad proteins, which amplifies the complexity of TGF-beta signaling.