View source for TGF alpha

{{Infobox_gene}}
'''Transforming growth factor alpha''' ('''TGF-α''') is a [[protein]] that in humans is encoded by the TGFA [[gene]].<ref name="entrez"/> As a member of the [[epidermal growth factor]] (EGF) family, TGF-α is a mitogenic [[polypeptide]].<ref name="Ojeda">{{cite journal |last1=Ojeda |first1=S. R. |last2=Ma |first2=Y. J. |last3=Rage |first3=F. |date=September 1997 |title=The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty |journal=Molecular Psychiatry |volume=2 |issue=5 |pages=355–358 |doi=10.1038/sj.mp.4000307 |pmid=9322223}}</ref> 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 (biochemistry)|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.<ref name="entrez">{{cite web |title=Entrez Gene: TGFA transforming growth factor alpha |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7039}}</ref>

==Synthesis==
TGF-α is synthesized internally as part of a 160 (human) or 159 (rat) amino acid transmembrane precursor.<ref name=Ferrer>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.</ref> 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.<ref name=Ferrer/> 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.<ref name=Coffey>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.</ref> TGF-α has been shown to inhibit gastric acid secretion.<ref name=Coffey/>

Limited success has resulted from attempts to synthesize of a reductant molecule to TGF-α that displays a similar biological profile.<ref name="McInnes">{{cite journal |last1=McInnes |first1=C |last2=Wang |first2=J |last3=Al Moustafa |first3=AE |last4=Yansouni |first4=C |last5=O'Connor-McCourt |first5=M |last6=Sykes |first6=BD |year=1998 |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". |url= |journal=J. Biol. Chem.|volume=273 |issue=42 |pages=27357–63 |doi=10.1074/jbc.273.42.27357}}</ref>

===Synthesis in the stomach===
In the stomach, TGF-α is manufactured within the normal gastric mucosa.<ref name=Coffey/> TGF-α has been shown to inhibit gastric acid secretion.<ref name=Coffey/>

== Function ==
TGF-α can be produced in [[macrophages]], [[brain cells]], and [[keratinocyte]]s.  TGF-α induces [[epithelium|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.<ref name="McInnes"/> 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.<ref name=Ferrer/>

TGFα has also been shown to stimulate [[neuron|neural]] cell [[cell growth|proliferation]] in the [[adult]] injured [[brain]].<ref name = "Fallon_2000">{{cite journal |authors=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=14686–91 |year=2000 |pmid=11121069 |pmc=18979 |doi=10.1073/pnas.97.26.14686}}</ref>

==Receptor==
A 170-kDa glycosylated [[protein]] known as the EGF receptor binds to TGF-α allowing the [[polypeptide]] to function in various signaling pathways.<ref name=Ojeda/> 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.<ref name=Ojeda/> As a membrane anchored-growth factor, TGF-α can be cleaved from an integral membrane glycoprotein via a protease.<ref name=Ferrer/>  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.png|thumb|left| [[Epidermal growth factor receptor]] (EGFR) signaling pathway upon binding to TGF-α.]]

== Animal studies ==

In an animal model of [[Parkinson's disease]] where [[dopaminergic neuron]]s have been damaged by [[6-hydroxydopamine]], infusion of TGF-α into the brain caused an increase in the number of neuronal precursor cells.<ref name = "Fallon_2000"/> However TGF-α treatment did not result in neurogenesis dopaminergic neurons.<ref name="pmid15483111">{{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 = J. Neurosci. | volume = 24 | issue = 41 | pages = 8924–31 |date=October 2004  | pmid = 15483111 | pmc = 2613225 | doi = 10.1523/JNEUROSCI.2344-04.2004 | url = }}</ref>

== 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.<ref name=Ojeda/>  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.<ref name=Ojeda/>

===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.<ref name=Hao>Hao, H.; Schwaber, J. Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. ''Brain Res''. 2006, 1088, 45.</ref>  Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.<ref name=Hao/>

===Tumors===
Its potential use as a prognostic biomarker in various tumors, like [[gastric carcinoma]].<ref name=" pmid = 22582975 ">{{cite journal |author=Fanelli MF |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 |date=Aug 2012 |pmid=22582975 |url= |doi=10.1111/j.1365-2559.2011.04139.x |pages=153–61}}</ref> or [[melanoma]] has been suggested.<ref name=" pmid = 24457057 ">{{cite journal |author=Tarhini AA |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=J Transl Med |volume=12 |issue= |date=Jan 2014 |doi=10.1186/1479-5876-12-19 |pmc=3909384 |pmid=24457057}}</ref> Elevated TGF-α is associated with [[Ménétrier's disease|Menetrier's disease]], a precancerous condition of the stomach.<ref>{{cite journal |last1=Coffey |first1=Robert J. |last2=Washington |first2=Mary Kay |last3=Corless |first3=Christopher L. |last4=Heinrich |first4=Michael C. |date=2007 |title=Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach |journal=Journal of Clinical Investigation |volume=117 |issue=1 |pages=70–80 |doi=10.1172/JCI30491 |pmc=1716220 |pmid=17200708 |url=http://www.jci.org/articles/view/30491 |access-date=2016-03-25}}</ref>

== Interactions ==

TGF alpha has been shown to [[Protein-protein interaction|interact]] with [[GORASP1]]<ref name="pmid11739402">{{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 = J. Cell Biol. | volume = 155 | issue = 6 | pages = 885–91 |date=December 2001 | pmid = 11739402 | pmc = 2150891 | doi = 10.1083/jcb.200108102 | url =   }}</ref> and [[GORASP2]].<ref name=pmid11739402/>

== See also ==
* [[Transforming growth factor]]

== References ==
{{Reflist}}

== Further reading ==
{{Refbegin | 2}}
*{{cite journal |vauthors=Luetteke NC, Lee DC | title = Transforming growth factor alpha: expression, regulation and biological action of its integral membrane precursor | journal = Semin. Cancer Biol. | volume = 1 | issue = 4 | pages = 265–75 | year = 1991 | pmid = 2103501 | doi =  }}
*{{cite journal |vauthors=Greten FR, Wagner M, Weber CK, Zechner U, Adler G, Schmid RM | title = TGF alpha transgenic mice. A model of pancreatic cancer development | journal = Pancreatology | volume = 1 | issue = 4 | pages = 363–8 | year = 2002 | pmid = 12120215 | doi = 10.1159/000055835 }}
*{{cite journal | author = Vieira AR | title = Association between the transforming growth factor alpha gene and nonsyndromic oral clefts: a HuGE review | journal = Am. J. Epidemiol. | volume = 163 | issue = 9 | pages = 790–810 | year = 2006 | pmid = 16495466 | doi = 10.1093/aje/kwj103 }}
*{{cite journal |vauthors=Nasim MM, Thomas DM, Alison MR, Filipe MI | title = Transforming growth factor alpha expression in normal gastric mucosa, intestinal metaplasia, dysplasia and gastric carcinoma--an immunohistochemical study | journal = Histopathology | volume = 20 | issue = 4 | pages = 339–43 | year = 1992 | pmid = 1577411 | doi = 10.1111/j.1365-2559.1992.tb00991.x }}
*{{cite journal |vauthors=Thomas DM, Nasim MM, Gullick WJ, Alison MR | title = Immunoreactivity of transforming growth factor alpha in the normal adult gastrointestinal tract | journal = Gut | volume = 33 | issue = 5 | pages = 628–31 | year = 1992 | pmid = 1612477 | pmc = 1379291 | doi = 10.1136/gut.33.5.628 }}
*{{cite journal |vauthors=Bean MF, Carr SA | title = Characterization of disulfide bond position in proteins and sequence analysis of cystine-bridged peptides by tandem mass spectrometry | journal = Anal. Biochem. | volume = 201 | issue = 2 | pages = 216–26 | year = 1992 | pmid = 1632509 | doi = 10.1016/0003-2697(92)90331-Z }}
*{{cite journal |vauthors=Lei ZM, Rao CV | title = Expression of epidermal growth factor (EGF) receptor and its ligands, EGF and transforming growth factor-alpha, in human fallopian tubes | journal = Endocrinology | volume = 131 | issue = 2 | pages = 947–57 | year = 1992 | pmid = 1639032 | doi = 10.1210/en.131.2.947 }}
*{{cite journal |vauthors=Werner S, Roth WK, Bates B, Goldfarb M, Hofschneider PH | title = Fibroblast growth factor 5 proto-oncogene is expressed in normal human fibroblasts and induced by serum growth factors | journal = Oncogene | volume = 6 | issue = 11 | pages = 2137–44 | year = 1991 | pmid = 1658709 | doi =  }}
*{{cite journal |vauthors=Saeki T, Cristiano A, Lynch MJ, Brattain M, Kim N, Normanno N, Kenney N, Ciardiello F, Salomon DS | title = Regulation by estrogen through the 5'-flanking region of the transforming growth factor alpha gene | journal = Mol. Endocrinol. | volume = 5 | issue = 12 | pages = 1955–63 | year = 1992 | pmid = 1791840 | doi = 10.1210/mend-5-12-1955  }}
*{{cite journal |vauthors=Harvey TS, Wilkinson AJ, Tappin MJ, Cooke RM, Campbell ID | title = The solution structure of human transforming growth factor alpha | journal = Eur. J. Biochem. | volume = 198 | issue = 3 | pages = 555–62 | year = 1991 | pmid = 2050136 | doi = 10.1111/j.1432-1033.1991.tb16050.x  }}
*{{cite journal |vauthors=Kline TP, Brown FK, Brown SC, Jeffs PW, Kopple KD, Mueller L | title = Solution structures of human transforming growth factor alpha derived from 1H NMR data | journal = Biochemistry | volume = 29 | issue = 34 | pages = 7805–13 | year = 1991 | pmid = 2261437 | doi = 10.1021/bi00486a005 }}
*{{cite journal |vauthors=Jakowlew SB, Kondaiah P, Dillard PJ, Sporn MB, Roberts AB | title = A novel low molecular weight ribonucleic acid (RNA) related to transforming growth factor alpha messenger RNA | journal = Mol. Endocrinol. | volume = 2 | issue = 11 | pages = 1056–63 | year = 1989 | pmid = 2464748 | doi = 10.1210/mend-2-11-1056 }}
*{{cite journal |vauthors=Jakobovits EB, Schlokat U, Vannice JL, Derynck R, Levinson AD | title = The human transforming growth factor alpha promoter directs transcription initiation from a single site in the absence of a TATA sequence | journal = Mol. Cell. Biol. | volume = 8 | issue = 12 | pages = 5549–54 | year = 1989 | pmid = 2907605 | pmc = 365660 | doi =  }}
*{{cite journal |vauthors=Tricoli JV, Nakai H, Byers MG, Rall LB, Bell GI, Shows TB | title = The gene for human transforming growth factor alpha is on the short arm of chromosome 2 | journal = Cytogenet. Cell Genet. | volume = 42 | issue = 1–2 | pages = 94–8 | year = 1986 | pmid = 3459638 | doi = 10.1159/000132258 }}
*{{cite journal |vauthors=Lee DC, Rose TM, Webb NR, Todaro GJ | title = Cloning and sequence analysis of a cDNA for rat transforming growth factor-alpha | journal = Nature | volume = 313 | issue = 6002 | pages = 489–91 | year = 1985 | pmid = 3855503 | doi = 10.1038/313489a0 }}
*{{cite journal |vauthors=Derynck R, Roberts AB, Winkler ME, Chen EY, Goeddel DV | title = Human transforming growth factor-alpha: precursor structure and expression in E. coli | journal = Cell | volume = 38 | issue = 1 | pages = 287–97 | year = 1984 | pmid = 6088071 | doi = 10.1016/0092-8674(84)90550-6 }}
*{{cite journal |vauthors=Ogbureke KU, MacDaniel RK, Jacob RS, Durban EM | title = Distribution of immunoreactive transforming growth factor-alpha in non-neoplastic human salivary glands | journal = Histol. Histopathol. | volume = 10 | issue = 3 | pages = 691–6 | year = 1995 | pmid = 7579819 | doi =  }}
*{{cite journal |vauthors=Walz TM, Malm C, Nishikawa BK, Wasteson A | title = Transforming growth factor-alpha (TGF-alpha) in human bone marrow: demonstration of TGF-alpha in erythroblasts and eosinophilic precursor cells and of epidermal growth factor receptors in blastlike cells of myelomonocytic origin | journal = Blood | volume = 85 | issue = 9 | pages = 2385–92 | year = 1995 | pmid = 7727772 | doi =  }}
*{{cite journal |vauthors=Patel B, Hiscott P, Charteris D, Mather J, McLeod D, Boulton M | title = Retinal and preretinal localisation of epidermal growth factor, transforming growth factor alpha, and their receptor in proliferative diabetic retinopathy | journal = The British Journal of Ophthalmology | volume = 78 | issue = 9 | pages = 714–8 | year = 1994 | pmid = 7947554 | pmc = 504912 | doi = 10.1136/bjo.78.9.714 }}
{{Refend}}

==External links==
* {{MeshName|Transforming+Growth+Factor+alpha}}

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{{Signaling proteins}}
{{Growth factor receptor modulators}}

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