TGF alpha

Template:Short description Template:Cs1 config Template:Infobox gene 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 (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to receptors capable of protein kinase 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. 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. TGF-α has been shown to inhibit gastric acid secretion.

Function

TGF-α can be produced in macrophages, brain cells, 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 neural cell proliferation in the adult injured brain.

Receptor

A 170-kDa glycosylated protein known as the EGF receptor binds to TGF-α allowing the polypeptide 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.

File:EGFR signaling pathway.svg

Epidermal growth factor receptor (EGFR) signaling pathway upon binding to TGF-α.

Animal studies

In an animal model of Parkinson's disease where dopaminergic neurons have been damaged by 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 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. 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 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 interact with GORASP1 and GORASP2.

See also

• Transforming growth factor

External links

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.