Transforming growth factor-α
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Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the
epidermal growth factor Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds. EGF was originally descr ...
(EGF) family, TGF-α is a mitogenic
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
. The protein becomes activated when binding to receptors capable of protein
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
activity for cellular signaling. TGF-α is a transforming growth factor that is a ligand for the epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. This protein may act as either a transmembrane-bound ligand or a soluble ligand. This gene has been associated with many types of cancers, and it may also be involved in some cases of cleft lip/palate.


Synthesis

TGF-α is synthesized internally as part of a 160 (human) or 159 (rat) amino acid transmembrane precursor.Ferrer, I.; Alcantara, S.; Ballabriga, J.; Olive, M.; Blanco, R.; Rivera, R.; Carmona, M.; Berruezo, M.; Pitarch, S.; Planas, A. Transforming growth factor- α (TGF-α) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain. Prog. Neurobiol. 1996, 49, 99. The precursor is composed of an extracellular domain containing a hydrophobic transmembrane domain, 50 amino acids of TGF-α, and a 35-residue-long cytoplasmic domain. In its smallest form, TGF-α has six cysteines linked together via three disulfide bridges. Collectively, all members of the EGF/TGF-α family share this structure. The protein, however, is not directly related to TGF-β. Limited success has resulted from attempts to synthesize of a reductant molecule to TGF-α that displays a similar biological profile.


Synthesis in the stomach

In the stomach, TGF-α is manufactured within the normal gastric mucosa.Coffey, R.; Gangarosa, L.; Damstrup, L.; Dempsey, P. Basic actions of transforming growth factor- α and related peptides. Eur. J. Gastroen. Hepat. 1995, 7, 923. TGF-α has been shown to inhibit gastric acid secretion.


Function

TGF-α can be produced in macrophages,
brain cells Brain cells make up the functional tissue of the brain. The rest of the brain tissue is structural or connective called the stroma which includes blood vessels. The two main types of cells in the brain are neurons, also known as nerve cells, an ...
, and keratinocytes. TGF-α induces epithelial development. Considering that TGF-α is a member of the EGF family, the biological actions of TGF-α and EGF are similar. For instance, TGF-α and EGF bind to the same receptor. When TGF-α binds to EGFR it can initiate multiple cell proliferation events. Cell proliferation events that involve TGF-α bound to EGFR include wound healing and embryogenesis. TGF-α is also involved in tumerogenesis and believed to promote angiogenesis. TGF-α has also been shown to stimulate
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cell
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in the
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injured brain.


Receptor

A 170-kDa glycosylated protein known as the EGF receptor binds to TGF-α allowing the
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
to function in various signaling pathways. The EGF receptor is characterized by having an extracellular domain that has numerous amino acid motifs. EGFR is essential for a single transmembrane domain, an intracellular domain (containing tyrosine kinase activity), and ligand recognition. As a membrane anchored-growth factor, TGF-α can be cleaved from an integral membrane glycoprotein via a protease. Soluble forms of TGF-α resulting from the cleavage have the capacity to activate EGFR. EGFR can be activated from a membrane-anchored growth factor as well. When TGF-α binds to EGFR it dimerizes triggering phosphorylation of a protein-tyrosine kinase. The activity of protein-tyrosine kinase causes an autophosphorylation to occur among several tyrosine residues within EGFR, influencing activation and signaling of other proteins that interact in many signal transduction pathways.


Animal studies

In an animal model of Parkinson's disease where dopaminergic neurons have been damaged by
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, infusion of TGF-α into the brain caused an increase in the number of neuronal precursor cells. However TGF-α treatment did not result in neurogenesis of dopaminergic neurons.


Human studies


Neuroendocrine system

The EGF/TGF-α family has been shown to regulate luteinizing hormone-releasing hormone (LHRH) through a glial-neuronal interactive process. Produced in hypothalamic astrocytes, TGF-α indirectly stimulates LHRH release through various intermediates. As a result, TGF-α is a physiological component essential to the initiation process of female puberty.


Suprachiasmatic nucleus

TGF-α has also been observed to be highly expressed in the suprachiasmatic nucleus (SCN) (5). This finding suggests a role for EGFR signaling in the regulation of CLOCK and circadian rhythms within the SCN.Hao, H.; Schwaber, J. Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. ''Brain Res''. 2006, 1088, 45. Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.


Tumors

This protein shows potential use as a prognostic biomarker in various tumors, like gastric carcinoma. or
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
has been suggested. Elevated TGF-α is associated with Menetrier's disease, a precancerous condition of the stomach.


Interactions

TGF alpha has been shown to
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with GORASP1 and
GORASP2 Golgi reassembly-stacking protein of 55 k Da (GRASP55) also known as golgi reassembly-stacking protein 2 (GORASP2) is a protein that in humans is encoded by the ''GORASP2'' gene. It was identified by its homology with GRASP65 and the protein's ...
.


See also

* Transforming growth factor


References


Further reading

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External links

* {{NLM content