TGF alpha

Transforming growth factor, alpha

PDB rendering based on 1mox.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TGFA ; TFGA
External IDs OMIM: 190170 MGI: 98724 HomoloGene: 2431 GeneCards: TGFA Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 7039 21802
Ensembl ENSG00000163235 ENSMUSG00000029999
UniProt P01135 P48030
RefSeq (mRNA) NM_001099691 NM_031199
RefSeq (protein) NP_001093161 NP_112476
Location (UCSC) Chr 2:
70.45 – 70.55 Mb		 Chr 6:
86.2 – 86.28 Mb
PubMed search

Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene.[1] As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide.[2] 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.[1]

Synthesis

TGF-α is synthesized internally as part of a 160 (human) or 159 (rat) amino acid transmembrane precursor.[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.[3] 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.[4] TGF-α has been shown to inhibit gastric acid secretion.[4]

Limited success has resulted from attempts to synthesize of a reductant molecule to TGF-α that displays a similar biological profile.[5]

Synthesis in the stomach

In the stomach, TGF-α is manufactured within the normal gastric mucosa.[4] TGF-α has been shown to inhibit gastric acid secretion.[4]

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.[5] 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.[3]

TGFα has also been shown to stimulate neural cell proliferation in the adult injured brain.[6]

TGF-α receptor

A 170-kDa glycosylated protein known as the EGF receptor binds to TGF-α allowing the polypeptide to function in various signaling pathways.[2] 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.[2] As a membrane anchored-growth factor, TGF-α can be cleaved from an integral membrane glycoprotein via a protease.[3] 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.[6] However TGF-α treatment did not result in neurogenesis dopaminergic neurons.[7]

Human studies

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.[2] 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.[2]

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.[8] Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.[8]

TGF-α and tumors

Its potential use as a prognostic biomarker in various tumors, like gastric carcinoma .[9] or melanoma has been suggested.[10] Elevated TGF-α is associated with Menetrier's disease, a precancerous condition of the stomach.[11]

Interactions

TGF alpha has been shown to interact with GORASP1[12] and GORASP2.[12]

See also

References

  1. 1 2 "Entrez Gene: TGFA transforming growth factor alpha".
  2. 1 2 3 4 5 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.
  3. 1 2 3 4 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.
  4. 1 2 3 4 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.
  5. 1 2 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.
  6. 1 2 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.
  7. ↑ 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.
  8. 1 2 Hao, H.; Schwaber, J. Epidermal growth factor receptor induced Erk phosphorylation in the suprachiasmatic nucleus. Brain Res. 2006, 1088, 45.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 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.

Further reading

External links

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