TGF alpha

TGFA
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1GK5, 1MOX, 1YUF, 1YUG, 2TGF, 3E50, 3TGF, 4TGF
Identifiers
Aliases	TGFA, TFGA, transforming growth factor alpha, Transforming growth factor - α
External IDs	OMIM: 190170 MGI: 98724 HomoloGene: 2431 GeneCards: TGFA
Gene location (Human)
Chr.	Chromosome 2 (human)[1]
End	70,554,193 bp[1]
Gene location (Mouse)
Chr.	Chromosome 6 (mouse)[2]
End	86,275,719 bp[2]
RNA expression pattern
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	• epidermal growth factor receptor binding; • GO:0001948 protein binding; • growth factor activity;
Cellular component	• integral component of membrane; • endoplasmic reticulum membrane; • membrane; • cell membrane; • integral component of plasma membrane; • extracellular region; • cell surface; • basolateral plasma membrane; • perinuclear region of cytoplasm; • ER to Golgi transport vesicle membrane; • endoplasmic reticulum-Golgi intermediate compartment membrane; • cytoplasmic vesicle; • Golgi membrane; • extracellular; • clathrin-coated vesicle membrane;
Biological process	• positive regulation of epidermal growth factor-activated receptor activity; • positive regulation of epithelial cell proliferation; • ER to Golgi vesicle-mediated transport; • COPII vesicle coating; • activation of MAPK activity; • cellular proliferation; • positive regulation of mitotic nuclear division; • positive regulation of cell division; • regulation of transcription from RNA polymerase II promoter; • epidermal growth factor receptor signaling pathway; • positive regulation of cell proliferation; • MAPK cascade; • signal transduction; • negative regulation of epidermal growth factor receptor signaling pathway; • positive regulation of protein kinase B signaling; • membrane organization; • intracellular signal transduction;
	Sources:Amigo / QuickGO
Orthologs
	7039
	21802
	ENSG00000163235
	ENSMUSG00000029999
	P01135
	P48030
	NM_001099691; NM_001308158; NM_001308159; NM_003236
	NM_031199
	NP_001093161; NP_001295087; NP_001295088; NP_003227
	NP_112476
	Wikidata
View/Edit Human	View/Edit Mouse

Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene.[5] As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide.[6] 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.[5]

Synthesis

TGF-α is synthesized internally as part of a 160 (human) or 159 (rat) amino acid transmembrane precursor.[7] 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.[7] 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.[8]

Synthesis in the stomach

In the stomach, TGF-α is manufactured within the normal gastric mucosa.[9] 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.[8] 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.[7]

TGF-α has also been shown to stimulate neural cell proliferation in the adult injured brain.[10]

Receptor

A 170-kDa glycosylated protein known as the EGF receptor binds to TGF-α allowing the polypeptide to function in various signaling pathways.[6] 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.[6] As a membrane anchored-growth factor, TGF-α can be cleaved from an integral membrane glycoprotein via a protease.[7] 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.

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.[10] However TGF-α treatment did not result in neurogenesis dopaminergic neurons.[11]

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.[6] 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.[6]

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.[12] Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.[12]

Tumors

This protein shows potential use as a prognostic biomarker in various tumors, like gastric carcinoma.[13] or melanoma has been suggested.[14] Elevated TGF-α is associated with Menetrier's disease, a precancerous condition of the stomach.[15]

Interactions

TGF alpha has been shown to interact with GORASP1[16] and GORASP2.[16]

References

GRCh38: Ensembl release 89: ENSG00000163235 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000029999 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Entrez Gene: TGFA transforming growth factor alpha".
Ojeda, S. R.; Ma, Y. J.; Rage, F. (September 1997). "The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty". Molecular Psychiatry. 2 (5): 355–358. doi:10.1038/sj.mp.4000307. PMID 9322223.
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.
McInnes, C; Wang, J; Al Moustafa, AE; Yansouni, C; O'Connor-McCourt, M; Sykes, BD (1998). "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"". J. Biol. Chem. 273 (42): 27357–63. doi:10.1074/jbc.273.42.27357.
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.
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 (2000). "In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain". Proceedings of the National Academy of Sciences of the United States of America. 97 (26): 14686–91. doi:10.1073/pnas.97.26.14686. PMC 18979. PMID 11121069.CS1 maint: uses authors parameter (link)
Cooper O, Isacson O (October 2004). "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". J. Neurosci. 24 (41): 8924–31. doi:10.1523/JNEUROSCI.2344-04.2004. PMC 2613225. PMID 15483111.
Hao, H.; Schwaber, J. Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. Brain Res. 2006, 1088, 45.
Fanelli MF (Aug 2012). "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". Histopathology. 61 (2): 153–61. doi:10.1111/j.1365-2559.2011.04139.x. PMID 22582975.
Tarhini AA (Jan 2014). "A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma". J Transl Med. 12. doi:10.1186/1479-5876-12-19. PMC 3909384. PMID 24457057.
Coffey, Robert J.; Washington, Mary Kay; Corless, Christopher L.; Heinrich, Michael C. (2007). "Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach". Journal of Clinical Investigation. 117 (1): 70–80. doi:10.1172/JCI30491. PMC 1716220. PMID 17200708. Retrieved 2016-03-25.
Barr FA, Preisinger C, Kopajtich R, Körner R (December 2001). "Golgi matrix proteins interact with p24 cargo receptors and aid their efficient retention in the Golgi apparatus". J. Cell Biol. 155 (6): 885–91. doi:10.1083/jcb.200108102. PMC 2150891. PMID 11739402.

External links

Transforming+Growth+Factor+alpha at the US National Library of Medicine Medical Subject Headings (MeSH)

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

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000163235 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000029999 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: TGFA transforming growth factor alpha".

[Ojeda-6] Ojeda, S. R.; Ma, Y. J.; Rage, F. (September 1997). "The transforming growth factor alpha gene family is involved in the neuroendocrine control of mammalian puberty". Molecular Psychiatry. 2 (5): 355–358. doi:10.1038/sj.mp.4000307. PMID 9322223.

[Ferrer-7] 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.

[McInnes-8] McInnes, C; Wang, J; Al Moustafa, AE; Yansouni, C; O'Connor-McCourt, M; Sykes, BD (1998). "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"". J. Biol. Chem. 273 (42): 27357–63. doi:10.1074/jbc.273.42.27357.

[Coffey-9] 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.

[Fallon_2000-10] 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 (2000). "In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain". Proceedings of the National Academy of Sciences of the United States of America. 97 (26): 14686–91. doi:10.1073/pnas.97.26.14686. PMC 18979. PMID 11121069.CS1 maint: uses authors parameter (link)

[pmid15483111-11] Cooper O, Isacson O (October 2004). "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". J. Neurosci. 24 (41): 8924–31. doi:10.1523/JNEUROSCI.2344-04.2004. PMC 2613225. PMID 15483111.

[Hao-12] Hao, H.; Schwaber, J. Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. Brain Res. 2006, 1088, 45.

[pmid_=_22582975-13] Fanelli MF (Aug 2012). "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". Histopathology. 61 (2): 153–61. doi:10.1111/j.1365-2559.2011.04139.x. PMID 22582975.

[pmid_=_24457057-14] Tarhini AA (Jan 2014). "A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma". J Transl Med. 12. doi:10.1186/1479-5876-12-19. PMC 3909384. PMID 24457057.

[15] Coffey, Robert J.; Washington, Mary Kay; Corless, Christopher L.; Heinrich, Michael C. (2007). "Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach". Journal of Clinical Investigation. 117 (1): 70–80. doi:10.1172/JCI30491. PMC 1716220. PMID 17200708. Retrieved 2016-03-25.

[pmid11739402-16] Barr FA, Preisinger C, Kopajtich R, Körner R (December 2001). "Golgi matrix proteins interact with p24 cargo receptors and aid their efficient retention in the Golgi apparatus". J. Cell Biol. 155 (6): 885–91. doi:10.1083/jcb.200108102. PMC 2150891. PMID 11739402.