TGF alpha

Transforming growth factor alpha (TGF-α) is a is_associated_with::protein that in humans is encoded by the TGFA is_associated_with::gene. As a member of the is_associated_with::epidermal growth factor (EGF) family, TGF-α is a mitogenic is_associated_with::polypeptide. The protein becomes activated when binding to receptors capable of protein is_associated_with::kinase activity for cellular signaling.

TGF-α is a is_associated_with::transforming growth factor that is a ligand for the is_associated_with::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. 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. In the stomach, TGF-α is manufactured within the normal gastric mucosa. TGF-α has been shown to inhibit gastric acid secretion.

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. TGF-α has been shown to inhibit gastric acid secretion.

Function
TGF-α can be produced in is_associated_with::macrophages, is_associated_with::brain cells, and is_associated_with::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.

TGFα has also been shown to stimulate neural cell proliferation in the is_associated_with::adult injured is_associated_with::brain.

TGF-α receptor
A 170-kDa glycosylated is_associated_with::protein known as the EGF receptor binds to TGF-α allowing the is_associated_with::polypeptide to function in various signaling pathways. The EGF receptor is characterized by having an extracellular domain that has numerous is_associated_with::amino acid motifs. EGFR is characterized by having an extracellular domain made up of numerous is_associated_with::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 is_associated_with::Parkinson's disease where is_associated_with::dopaminergic neurons have been damaged by is_associated_with::6-hydroxydopamine, 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 dopaminergic neurons.

TGF-α and the 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.

TGF-α and the 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. Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.

TGF-α and tumors
Its potential use as a prognostic biomarker in various tumors, like is_associated_with::gastric carcinoma. or is_associated_with::melanoma has been suggested.

Interactions
TGF alpha has been shown to interact with is_associated_with::GORASP1 and is_associated_with::GORASP2.