TGF alpha

TGF-α is synthesized internally as part of a 160 (human) or 159 (rat) amino acid transmembrane precursor.{{cite journal | vauthors = Ferrer I, Alcántara S, Ballabriga J, Olivé M, Blanco R, Rivera R, Carmona M, Berruezo M, Pitarch S, Planas AM | title = Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain | journal = Progress in Neurobiology | volume = 49 | issue = 2 | pages = 99–123 | date = June 1996 | pmid = 8844822 | doi = 10.1016/0301-0082(96)00009-3 }} 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.{{cite journal | vauthors = McInnes C, Wang J, Al Moustafa AE, Yansouni C, O'Connor-McCourt M, Sykes BD | title = Structure-based minimization of transforming growth factor-alpha (TGF-alpha) through NMR analysis of the receptor-bound ligand. Design, solution structure, and activity of TGF-alpha 8-50 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 42 | pages = 27357–27363 | date = October 1998 | pmid = 9765263 | doi = 10.1074/jbc.273.42.27357 | doi-access = free }}

In the stomach, TGF-α is manufactured within the normal gastric mucosa.{{cite journal | vauthors = Coffey RJ, Gangarosa LM, Damstrup L, Dempsey PJ | title = Basic actions of transforming growth factor-alpha and related peptides | journal = European Journal of Gastroenterology & Hepatology | volume = 7 | issue = 10 | pages = 923–7 | date = October 1995 | pmid = 8590135 | doi = 10.1097/00042737-199510000-00003 }} TGF-α has been shown to inhibit gastric acid secretion.

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.{{cite journal | vauthors = Fallon J, Reid S, Kinyamu R, Opole I, Opole R, Baratta J, Korc M, Endo TL, Duong A, Nguyen G, Karkehabadhi M, Twardzik D, Patel S, Loughlin S | title = In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 26 | pages = 14686–14691 | date = December 2000 | pmid = 11121069 | pmc = 18979 | doi = 10.1073/pnas.97.26.14686 | doi-access = free | bibcode = 2000PNAS...9714686F }}

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 (EGFR) signaling pathway upon binding to TGF-α.]]

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.{{cite journal | vauthors = Cooper O, Isacson O | title = Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons | journal = The Journal of Neuroscience | volume = 24 | issue = 41 | pages = 8924–8931 | date = October 2004 | pmid = 15483111 | pmc = 2613225 | doi = 10.1523/JNEUROSCI.2344-04.2004 }}

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 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.{{cite journal | vauthors = Hao H, Schwaber J | title = Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus | journal = Brain Research | volume = 1088 | issue = 1 | pages = 45–8 | date = May 2006 | pmid = 16630586 | doi = 10.1016/j.brainres.2006.02.100 }} Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.

This protein shows potential use as a prognostic biomarker in various tumors, like gastric carcinoma.{{cite journal | vauthors = Fanelli MF, Chinen LT, Begnami MD, Costa WL, Fregnami JH, Soares FA, Montagnini AL | title = The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer | journal = Histopathology | volume = 61 | issue = 2 | pages = 153–161 | date = August 2012 | pmid = 22582975 | doi = 10.1111/j.1365-2559.2011.04139.x | s2cid = 6566296 }} or melanoma has been suggested.{{cite journal | vauthors = Tarhini AA, Lin Y, Yeku O, LaFramboise WA, Ashraf M, Sander C, Lee S, Kirkwood JM | title = A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma | journal = Journal of Translational Medicine | volume = 12 | pages = 19 | date = January 2014 | pmid = 24457057 | pmc = 3909384 | doi = 10.1186/1479-5876-12-19 | doi-access = free }} Elevated TGF-α is associated with Menetrier's disease, a precancerous condition of the stomach.{{cite journal | vauthors = Coffey RJ, Washington MK, Corless CL, Heinrich MC | title = Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach | journal = The Journal of Clinical Investigation | volume = 117 | issue = 1 | pages = 70–80 | date = January 2007 | pmid = 17200708 | pmc = 1716220 | doi = 10.1172/JCI30491 }}

TGF alpha has been shown to interact with GORASP1{{cite journal | vauthors = Barr FA, Preisinger C, Kopajtich R, Körner R | title = Golgi matrix proteins interact with p24 cargo receptors and aid their efficient retention in the Golgi apparatus | journal = The Journal of Cell Biology | volume = 155 | issue = 6 | pages = 885–891 | date = December 2001 | pmid = 11739402 | pmc = 2150891 | doi = 10.1083/jcb.200108102 }} and GORASP2.

• Transforming growth factor

{{Reflist}}

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{{Refend}}

• {{MeshName|Transforming+Growth+Factor+alpha}}

{{PDB Gallery|geneid=7039}}

{{Signaling proteins}}

{{Growth factor receptor modulators}}

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