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Transforming Growth Factor Beta Receptor 1

This page is about the transforming growth factor beta receptor 1, a protein important to signal the actions of the transforming growth factor 1.

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Function

The transforming growth factor beta receptor 1 (TGFBR1) is a receptor for the transforming growth factor beta (TGF-β), which is part of the TGF-cytokine superfamily of proteins. This superfamily consists of bone morphogenic proteins, activins and TGF-βs and is important in physiology, homeostasis and development, controlling proliferation, differentiation and other functions. The signaling of TGF-β depends on two transmembrane serine/threonine kinase receptors: TGFBR1 and TGFBR2, the former of which is discussed here [1] [2].

TGFBR1 is a protein responsible for the action signal initiation of the transforming growth factor beta by phosphorylating cytoplasmic proteins Smads at the C-terminus, causing these proteins to form a heteromeric complex. This complex will move to the nucleus to regulate the transcription of genes related to this factor, such as genes that promote proliferation, differentiation, apoptosis or cell migration, and the development of fibrosis in several organs, among others. This receptor is the product of the translation and transcription of the TGFBR1 gene, also known as ALK5, which is located at the position 22.33 on the long arm (q) of chromosome 9 of organisms belonging to the Homo sapiens species (Human). This gene is expressed through all the body, although it is found more abundantly in the placenta and just barely in the brain and the heart.

Structural Highlights

This protein is an activin-type kinase receptor that belongs to the heterotetrameric receptor complex, which is constituted by two units of this protein and two beta 2 receptors, to which the transforming growth factor binds. This beta receptor 1 has a similar structure to that of the beta 2 receptor, with both being transmembrane serine/threonine kinase receptors and presenting an extracellular cysteine-rich involved in ligand binding, a transmembrane helix, and an intracellular C-terminal cytoplasmic kinase domain [3]. The kinase domain, mostly a helix, shows an inactive conformation, distorting and, thus, damaging the integrity of the ATP-binding site by constricting the phosphate and magnesium recognition pocket.

In its N-terminal, the beta receptor 1 possess a smaller N lobe, a larger C lobe, and a GS region/domain. The N lobe, dominated by a twisted, five-stranded β sheet, is involved in ATP binding while it also contains an insertion between strands β4 and β5 (the L45 loop, that extends out into solution to interact with other protein) that determines Smad substrate specificity. At the same time, the C lobe, largely helical (and therefore called alfa C helix), is required for substrate recognition, whereas the GS region is a regulatory segment.

This segment is formed by the alfa GS1 helix, which is amphiphilic, and the alfa GS2 helix, which is the hydrophobic core of the protein. This second helix is in contact with both the beta sheet of N lobe and the first helix, which connects to the C lobe - thus, making the GS segment a region located between the two lobes of the N-terminal. In turn, the connection of the two helices is made by a loop composed by a conserved sequence of . This loop is the most important region of the beta receptor 1 for it is the region phosphorylated in its serine and threonine residues by the beta 2 receptor of the heterotetrameric complex when linked to the growth factor. This way, the beta receptor 1 is activated and, in turn, transmits the factor signal, which causes the phosphorylation and therefore activation of Smad transcription factors. Studies claim that the substitution of the Thr residue of this loop with aspartate or glutamate turns the beta receptor 1 constitutively active, meaning it would not depend on phosphorylation by the beta 2 receptor to function.

The activation segment of this protein is a beta hairpin composed by the strands beta 9 and beta 10, supported by the alfa F helix extension of the C-terminal. Together with beta 6, this activation segment forms a stranded sheet that stabilizes the rotated conformation of the C lobe. This stabilization is done by the van der Walls interactions, between from the C lobe and Ile-329 and Pro-327 from the beta 6, and hydrogen bonds between Arg-357 from C lobe and Thr-251 from beta 9. At the same time, it binds to the N lobe via van der Walls interactions between its aliphatic portion of Arg-372 and the beta sheet's side-chain of Phe-216. This side-chain of Phe-216 is a loop, known as the phosphate-binding loop of the protein, that connects beta 1 and beta 2. Unlike many receptor tyrosine kinases, the phosphorylation of the activation segment of TGFBR1 is not responsible for the activation of the protein. In this case, multiple phosphorylations in the GS region, upstream of the catalytic domain, are actually responsible for activation [4]. This mechanism is unique to this protein family and therefore there is no structural precedent to understand this molecular mechanism for activity control.

Diseases

Loeys-Dietz syndrome 1

Mutations in the TGFBR1 gene can result in the development of Loeys-Dietz syndrome 1 (LDS1). This type of aortic aneurysm syndrome, which is systemically widespread, is one of the most common Loeys-Dietz syndromes, along with type 2. It is internally characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate; and externally by prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel. Some patients may also have craniosynostosis, exotropia, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, and even problems in the immune system, including food allergies, asthma, and inflammatory disorders, such as eczema or inflammatory bowel disease [5]. This disease presents an autosomal dominant pattern of inheritance. However, about 75% of the cases happen because of new mutations and therefore manifest on individuals in families without the disease. This proportion may be explained by the fact that women with this disease are likely to have severe pregnancy complications, such as rupture of the gravid uterus and the arteries, either during pregnancy or just after childbirth. These complications reduce the survival rate of both mother and infant, which may be one of the reasons as to why this disease is rarely inherited despite its dominant behavior.

Cancer

Diverse mutations in ALK-5 can lead to multiple cancers as it is one of the most commonly altered signaling pathways in human cancer is the transforming growth factor beta [6][7]. Therefore, mutations in its receptors, specially TGFBR1, are associated with cancer development.

One of the types of cancer most associated with TGFBR1 mutations is the multiple self-healing squamous epithelioma (MSSE). This is a form of skin cancer, also known as the Ferguson-Smith disease, characterized by the formation of multiple invasive and painless skin tumors that grow uncontrollably mostly in sun-exposed tissues for a few months, before shrinking and dying off for unknown reasons, leaving a deep and pitted scar [8]. This disease presents an autosomal dominant inheritance and is common in Scottish families. The symptoms extend through all one's life, though the age in which the first tumor appears is variable, happening between 8 and 62 years-old.

There is also evidence that points to the development of breast cancer due to mutation in the gene that encodes for this protein. TGFBR1*6A is a common hypomorphic variant of TGFBR1 and it has been particularly associated with increased risk for breast cancer, possibly accounting for approximately 5% of all breast cancer cases [9]. This allele is a common variant that sets itself apart by three alanine deletions within a stretch of nine alanines located in the 3′-end of exon 1 [10]. This mutation increases the risk of breast cancer by 11% for heterozygotes and 30% for homozygotes [11].


References

  1. ↑ Tebben AJ, Ruzanov M, Gao M, Xie D, Kiefer SE, Yan C, Newitt JA, Zhang L, Kim K, Lu H, Kopcho LM, Sheriff S. Crystal structures of apo and inhibitor-bound TGFbetaR2 kinase domain: insights into TGFbetaR isoform selectivity. Acta Crystallogr D Struct Biol. 2016 May;72(Pt 5):658-74. doi:, 10.1107/S2059798316003624. Epub 2016 Apr 26. PMID:27139629 doi:http://dx.doi.org/10.1107/S2059798316003624
  2. ↑ Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30. doi: 10.1038/nrm3434. Epub 2012, Sep 20. PMID:22992590 doi:http://dx.doi.org/10.1038/nrm3434
  3. ↑ Huse M, Chen YG, Massague J, Kuriyan J. Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12. Cell. 1999 Feb 5;96(3):425-36. PMID:10025408
  4. ↑ Wrana JL, Attisano L, Wieser R, Ventura F, Massague J. Mechanism of activation of the TGF-beta receptor. Nature. 1994 Aug 4;370(6488):341-7. doi: 10.1038/370341a0. PMID:8047140 doi:http://dx.doi.org/10.1038/370341a0
  5. ↑ Loeys-Dietz syndrome. Genetics Home Reference, U.S National Library of Medicine (2020). https://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome
  6. ↑ Akhurst RJ. TGF beta signaling in health and disease. Nat Genet. 2004 Aug;36(8):790-2. doi: 10.1038/ng0804-790. PMID:15284845 doi:http://dx.doi.org/10.1038/ng0804-790
  7. ↑ Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000 May 4;342(18):1350-8. doi: 10.1056/NEJM200005043421807. PMID:10793168 doi:http://dx.doi.org/10.1056/NEJM200005043421807
  8. ↑ D'Alessandro M, Coats SE, Morley SM, Mackintosh L, Tessari G, Turco A, Gerdes AM, Pichert G, Whittaker S, Brandrup F, Broesby-Olsen S, Gomez-Lira M, Girolomoni G, Maize JC, Feldman RJ, Kato N, Koga Y, Ferguson-Smith MA, Goudie DR, Lane EB. Multiple self-healing squamous epithelioma in different ethnic groups: more than a founder mutation disorder? J Invest Dermatol. 2007 Oct;127(10):2336-44. doi: 10.1038/sj.jid.5700914. Epub, 2007 Jun 7. PMID:17554363 doi:http://dx.doi.org/10.1038/sj.jid.5700914
  9. ↑ Moore-Smith L, Pasche B. TGFBR1 signaling and breast cancer. J Mammary Gland Biol Neoplasia. 2011 Jun;16(2):89-95. doi:, 10.1007/s10911-011-9216-2. Epub 2011 Apr 5. PMID:21461994 doi:http://dx.doi.org/10.1007/s10911-011-9216-2
  10. ↑ Pasche B, Knobloch TJ, Bian Y, Liu J, Phukan S, Rosman D, Kaklamani V, Baddi L, Siddiqui FS, Frankel W, Prior TW, Schuller DE, Agrawal A, Lang J, Dolan ME, Vokes EE, Lane WS, Huang CC, Caldes T, Di Cristofano A, Hampel H, Nilsson I, von Heijne G, Fodde R, Murty VV, de la Chapelle A, Weghorst CM. Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA. 2005 Oct 5;294(13):1634-46. doi: 10.1001/jama.294.13.1634. PMID:16204663 doi:http://dx.doi.org/10.1001/jama.294.13.1634
  11. ↑ Liao RY, Mao C, Qiu LX, Ding H, Chen Q, Pan HF. TGFBR1*6A/9A polymorphism and cancer risk: a meta-analysis of 13,662 cases and 14,147 controls. Mol Biol Rep. 2010 Oct;37(7):3227-32. doi: 10.1007/s11033-009-9906-7. Epub 2009, Nov 1. PMID:19882361 doi:http://dx.doi.org/10.1007/s11033-009-9906-7

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