TGF beta signaling pathway

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The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. [1] In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression. [2]

Contents

Mechanism

Ligand binding

TGF Beta ligand binds to receptor TGFbeta Pathway 1.svg
TGF Beta ligand binds to receptor

The TGF beta superfamily of ligands includes: bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), anti-Müllerian hormone (AMH), Activin, Nodal and TGFβs. [3] Signaling begins with the binding of a TGF beta superfamily ligand to a TGF beta type II receptor. The type II receptor is a serine/threonine receptor kinase, which catalyzes the phosphorylation of the Type I receptor. Each class of ligand binds to a specific type II receptor. [4] In mammals there are seven known type I receptors and five type II receptors. [5]

There are three activins: Activin A, Activin B and Activin AB. Activins are involved in embryogenesis and osteogenesis. They also regulate many hormones including pituitary, gonadal and hypothalamic hormones as well as insulin. They are also nerve cell survival factors.

The BMPs bind to the bone morphogenetic protein receptor type-2 (BMPR2). They are involved in a multitude of cellular functions including osteogenesis, cell differentiation, anterior/posterior axis specification, growth, and homeostasis.

The TGFβ family includes: TGFβ1, TGFβ2, TGFβ3. Like the BMPs, TGFβs are involved not only in embryogenesis and cell differentiation, but also in apoptosis and other functions. They bind to TGF-beta receptor type-2 (TGFBR2).

Nodal binds to activin A receptor, type IIB ACVR2B. It can then either form a receptor complex with activin A receptor, type IB (ACVR1B) or with activin A receptor, type IC (ACVR1C). [5]

When the receptor-ligand binding occurs via local action, this is classified as paracrine signalling.

Receptor recruitment and phosphorylation

Type II receptor recruits type I receptor and phosphorylates TGF beta pathway 2.svg
Type II receptor recruits type I receptor and phosphorylates

The TGF beta ligand binds to a type II receptor dimer, which recruits a type I receptor dimer forming a hetero-tetrameric complex with the ligand. [6] These receptors are serine/threonine kinase receptors. They have a cysteine rich extracellular domain, a transmembrane domain, and a cytoplasmic serine/threonine rich domain. The GS domain of the type I receptor consists of a series of about thirty serine-glycine repeats. [7] The binding of a TGFβ family ligand causes the rotation of the receptors so that their cytoplasmic kinase domains are arranged in a catalytically favorable orientation. The Type II receptor phosphorylates serine residues of the Type I receptor, which activates the protein.

SMAD phosphorylation

Type I receptor phosphorylates R-SMAD TGF beta pathway step3.svg
Type I receptor phosphorylates R-SMAD

There are five receptor regulated SMADs: SMAD1, SMAD2, SMAD3, SMAD5, and SMAD9 (sometimes referred to as SMAD8). There are essentially two intracellular pathways involving these R-SMADs. TGFβs, Activins, Nodals and some GDFs are mediated by SMAD2 and SMAD3, while BMPs, AMH and a few GDFs are mediated by SMAD1, SMAD5 and SMAD9. The binding of the R-SMAD to the type I receptor is mediated by a zinc double finger FYVE domain containing protein. Two such proteins that mediate the TGFβ pathway include SARA (the SMAD anchor for receptor activation) and HGS (Hepatocyte growth factor-regulated tyrosine kinase substrate).

SARA is present in an early endosome which, by clathrin-mediated endocytosis, internalizes the receptor complex. [8] SARA recruits an R-SMAD. SARA permits the binding of the R-SMAD to the L45 region of the Type I receptor. [9] SARA orients the R-SMAD such that serine residue on its C-terminus faces the catalytic region of the Type I receptor. The Type I receptor phosphorylates the serine residue of the R-SMAD. Phosphorylation induces a conformational change in the MH2 domain of the R-SMAD and its subsequent dissociation from the receptor complex and SARA. [10]

CoSMAD binding

R-SMAD binds coSMAD TGF beta Pathway step4.svg
R-SMAD binds coSMAD

The now phosphorylated RSMAD has high affinity for coSMAD (e.g. SMAD4) and forms a complex with one. The phosphate group does not act as a docking site for coSMAD, but rather the phosphorylation opens up an amino acid stretch allowing interaction.

Transcription

R-SMAD-coSMAD complex enters nucleus Pathwaystep5.svg
R-SMAD-coSMAD complex enters nucleus

The phosphorylated RSMAD/coSMAD complex enters the nucleus where it binds transcription promoters/cofactors and causes the transcription of DNA.

Bone morphogenetic proteins cause the transcription of mRNAs involved in osteogenesis, neurogenesis, and ventral mesoderm specification.

TGFβs cause the transcription of mRNAs involved in apoptosis, extracellular matrix neogenesis and immunosuppression. They are also involved in G1 arrest in the cell cycle.

Activin causes the transcription of mRNAs involved in gonadal growth, embryo differentiation and placenta formation.

Nodal causes the transcription of mRNAs involved in left and right axis specification, mesoderm and endoderm induction.

Pathway regulation

The TGF beta signaling pathway is involved in a wide range of cellular process and subsequently is very heavily regulated. There are a variety of mechanisms where the pathway is modulated either positively or negatively, including the agonists for ligands and R-SMADs, the decoy receptors, and the ubiquitination of R-SMADs and receptors.

Ligand agonists/antagonists

Both chordin and noggin are antagonists of BMPs. They bind BMPs preventing the binding of the ligand to the receptor. [11] It has been demonstrated that Chordin and Noggin dorsalize mesoderm. They are both found in the dorsal lip of Xenopus and convert otherwise epidermis specified tissue into neural tissue (see neurulation). Noggin plays a key role in cartilage and bone patterning. Mice Noggin-/- have excess cartilage and lacked joint formation. [11]

Members of the DAN family of proteins also antagonize TGF beta family members. They include Cerberus, DAN, and Gremlin. These proteins contain nine conserved cysteines which can form disulfide bridges. It is believed that DAN antagonizes GDF5, GDF6 and GDF7.

Follistatin inhibits Activin, which it binds. It directly affects follicle-stimulating hormone (FSH) secretion. Follistatin also is implicated in prostate cancers where mutations in its gene may preventing it from acting on activin which has anti-proliferative properties. [11]

Lefty is a regulator of TGFβ and is involved in the axis patterning during embryogenesis. It is also a member of the TGF superfamily of proteins. It is asymmetrically expressed in the left side of murine embryos and subsequently plays a role in left-right specification. Lefty acts by preventing the phosphorylation of R-SMADs. It does so through a constitutively active TGFβ type I receptor and through a process downstream of its activation. [12]

Drug-based antagonists have also been identified, such as SB431542, [13] which selectively inhibits ALK4, ALK5, and ALK7.

Receptor regulation

The transforming growth factor receptor 3 (TGFBR3) is the most abundant of the TGF-β receptors yet, [14] it has no known signaling domain. [15] It however may serve to enhance the binding of TGFβ ligands to TGFβ type II receptors by binding TGFβ and presenting it to TGFBR2. One of the downstream targets of TGF β signaling, GIPC, binds to its PDZ domain, which prevents its proteosomal degradation, which subsequently increases TGFβ activity. It may also serve as an inhibin coreceptor to ActivinRII. [11]

BMP and activin membrane bound inhibitor (BAMBI), has a similar extracellular domain as type I receptors. It lacks an intracellular serine/threonine protein kinase domain and hence is a pseudoreceptor. It binds to the type I receptor preventing it from being activated. It serves as a negative regulator of TGFβ signaling and may limit TGFβ expression during embryogeneis. It requires BMP signaling for its expression

FKBP12 binds the GS region of the type I receptor preventing phosphorylation of the receptor by the type II receptors. It is believed that FKBP12 and its homologs help to prevent type I receptor activation in the absence of a ligands, since ligand binding causes its dissociation.

R-SMAD regulation

Role of inhibitory SMADs

There are two other SMADs which complete the SMAD family, the inhibitory SMADs (I-SMADS), SMAD6 and SMAD7. They play a key role in the regulation of TGF beta signaling and are involved in negative feedback. Like other SMADs they have an MH1 and an MH2 domain. SMAD7 competes with other R-SMADs with the Type I receptor and prevents their phosphorylation. [11] [16] It resides in the nucleus and upon TGFβ receptor activation translocates to the cytoplasm where it binds the type I receptor. SMAD6 binds SMAD4 preventing the binding of other R-SMADs with the coSMAD. The levels of I-SMAD increase with TGFβ signaling suggesting that they are downstream targets of TGFβ signaling.

R-SMAD ubiquitination

The E3 ubiquitin-protein ligases SMURF1 and SMURF2 regulate the levels of SMADs. They accept ubiquitin from an E2 conjugating enzyme where they transfer ubiquitin to the RSMADs which causes their ubiquitination and subsequent proteosomal degradation. SMURF1 binds to SMAD1 and SMAD5 while SMURF2 binds SMAD1, SMAD2, SMAD3, SMAD6 and SMAD7. It [ clarification needed ] enhances the inhibitory action of SMAD7 while reducing the transcriptional activities of SMAD2.

Summary table

TGF-β ligands of H.sapiens highlighted in grey, of D.melanogaster ligands in pink, of C.elegans in yellow.

TGF-β superfamily ligandLigand inhibitorsType II ReceptorType I receptor R-SMADs coSMAD I-SMADs
Activin A Follistatin ACVR2A ACVR1B (ALK4) SMAD2, SMAD3 SMAD4 SMAD7
GDF1 ACVR2A ACVR1B (ALK4) SMAD2, SMAD3 SMAD4 SMAD7
GDF11 ACVR2B ACVR1B (ALK4), TGFβRI (ALK5) SMAD2, SMAD3 SMAD4 SMAD7
BMP2-8 Noggin, Chordin, DAN BMPR2 BMPR1A (ALK3), BMPR1B (ALK6) SMAD1 SMAD5, SMAD8 SMAD4 SMAD6, SMAD7
Nodal Lefty ACVR2B ACVR1B (ALK4), ACVR1C (ALK7) SMAD2, SMAD3 SMAD4 SMAD7
TGFβs LTBP1, THBS1, Decorin TGFβRII ACVRL1 (ALK1), TGFβRI (ALK5) SMAD2, SMAD3 SMAD4 SMAD7
Dpp Punt Tkv Mad Medea
Screw Punt Sax Mad Medea
myoglianin Wit Baboon dSmad2 Medea
dActivin Wit, Punt Baboon dSmad2 Medea
Gbb Wit, Punt Tkv, Sax Mad Medea
Daf-7 Daf-4 Daf-1 Daf-8, Daf-14 Daf-3
Dbl-1 Daf-4 Sma-6 Sma-2, Sma-3, Sma-4 Sma-4

Related Research Articles

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

<span class="mw-page-title-main">Transforming growth factor beta</span> Cytokine

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 2</span> Protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 3</span> Protein-coding gene in humans

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 4</span> Mammalian protein found in Homo sapiens

SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, which act as mediators of TGF-β signal transduction. The TGFβ family of cytokines regulates critical processes during the lifecycle of metazoans, with important roles during embryo development, tissue homeostasis, regeneration, and immune regulation.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 7</span> Protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.

R-SMADs are receptor-regulated SMADs. SMADs are transcription factors that transduce extracellular TGF-β superfamily ligand signaling from cell membrane bound TGF-β receptors into the nucleus where they activate transcription TGF-β target genes. R-SMADS are directly phosphorylated on their c-terminus by type 1 TGF-β receptors through their intracellular kinase domain, leading to R-SMAD activation.

Smads comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily, which are critically important for regulating cell development and growth. The abbreviation refers to the homologies to the Caenorhabditis elegans SMA and MAD family of genes in Drosophila.

<span class="mw-page-title-main">BMPR2</span> Protein-coding gene in the species Homo sapiens

Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase encoded by the BMPR2 gene. It binds bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signaling. BMPs are involved in a host of cellular functions including osteogenesis, cell growth and cell differentiation. Signaling in the BMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of a BMP type I receptor, which the type II receptor phosphorylates. The type I receptor phosphorylates an R-SMAD, a transcriptional regulator.

<span class="mw-page-title-main">ACVR1B</span> Protein-coding gene in humans

Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.

<span class="mw-page-title-main">ACVR1</span> Protein-coding gene

Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2. ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the bone morphogenic protein (BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to fibrodysplasia ossificans progressiva, a very rare progressive genetic disease characterized by heterotopic ossification of muscles, tendons and ligaments. It is a bone morphogenetic protein receptor, type 1.

<span class="mw-page-title-main">ACVR2A</span> Protein-coding gene in the species Homo sapiens

Activin receptor type-2A is a protein that in humans is encoded by the ACVR2A gene. ACVR2A is an activin type 2 receptor.

Bone morphogenetic protein receptors are serine-threonine kinase receptors. Transforming growth factor beta family proteins bind to these receptors. There are four bone morphogenetic protein receptors:

<span class="mw-page-title-main">Endoglin</span> Protein-coding gene in the species Homo sapiens

Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, making it an important protein for tumor growth, survival and metastasis of cancer cells to other locations in the body.

<span class="mw-page-title-main">GDF2</span> Protein-coding gene in the species Homo sapiens

Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene. GDF2 belongs to the transforming growth factor beta superfamily.

<span class="mw-page-title-main">Upstream and downstream (transduction)</span>

The upstream signaling pathway is triggered by the binding of a signaling molecule, a ligand, to a receiving molecule, a receptor. Receptors and ligands exist in many different forms, and only recognize/bond to particular molecules. Upstream extracellular signaling transduce a variety of intracellular cascades.

The Nodal signaling pathway is a signal transduction pathway important in regional and cellular differentiation during embryonic development.

<span class="mw-page-title-main">Ectoderm specification</span> Stage in embryonic development

In Xenopus laevis, the specification of the three germ layers occurs at the blastula stage. Great efforts have been made to determine the factors that specify the endoderm and mesoderm. On the other hand, only a few examples of genes that are required for ectoderm specification have been described in the last decade. The first molecule identified to be required for the specification of ectoderm was the ubiquitin ligase Ectodermin ; later, it was found that the deubiquitinating enzyme, FAM/USP9x, is able to overcome the effects of ubiquitination made by Ectodermin in Smad4. Two transcription factors have been proposed to control gene expression of ectodermal specific genes: POU91/Oct3/4 and FoxIe1/Xema. A new factor specific for the ectoderm, XFDL156, has shown to be essential for suppression of mesoderm differentiation from pluripotent cells.

The transforming growth factor beta (TGFβ) receptors are a family of serine/threonine kinase receptors involved in TGF beta signaling pathway. These receptors bind growth factor and cytokine signaling proteins in the TGF-beta family such as TGFβs, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activin and inhibin, myostatin, anti-Müllerian hormone (AMH), and NODAL.

The DAF-1 gene encodes for a cell surface Enzyme-linked receptor of TGF-beta signaling pathway in the worm Caenorhabditis elegans. DAF-1 is one of the type I receptor of TGF-beta pathway. DAF-1 acts as a receptor protein serine/threonine kinase, is activated by type II receptor Daf-4 phosphorylation after the ligand Daf-7 binds to the receptor heterotetramer, and then phosphorylates Daf-8 or Daf-14, the SMAD proteins in C. elegans.

References

  1. ↑ Huminiecki L, Goldovsky L, Freilich S, Moustakas A, Ouzounis C, Heldin CH (February 2009). "Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom". BMC Evolutionary Biology. 9 (1): 28. doi: 10.1186/1471-2148-9-28 . PMC   2657120 . PMID   19192293.
  2. ↑ Zi, Zhike (2019-07-12). "Molecular Engineering of the TGF-β Signaling Pathway". Journal of Molecular Biology. 431 (15): 2644–2654. doi:10.1016/j.jmb.2019.05.022. hdl: 21.11116/0000-0003-F2A7-F . ISSN   1089-8638. PMID   31121181. S2CID   163166017.
  3. ↑ "Prosite Documentation PDOC00223". Archived from the original on 2011-05-25. Retrieved 2006-07-01.
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  5. 1 2 Munir S, Xu G, Wu Y, Yang B, Lala PK, Peng C (July 2004). "Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells". The Journal of Biological Chemistry. 279 (30): 31277–86. doi: 10.1074/jbc.M400641200 . PMID   15150278.
  6. ↑ Wrana JL, Attisano L, Cárcamo J, Zentella A, Doody J, Laiho M, et al. (December 1992). "TGF beta signals through a heteromeric protein kinase receptor complex". Cell. 71 (6): 1003–14. doi:10.1016/0092-8674(92)90395-S. PMID   1333888. S2CID   54397586.
  7. ↑ "Pfam entry TGF_beta_GS" . Retrieved 2006-07-01.
  8. ↑ Runyan CE, Schnaper HW, Poncelet AC (March 2005). "The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells". The Journal of Biological Chemistry. 280 (9): 8300–8. doi: 10.1074/jbc.M407939200 . PMID   15613484.
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  10. ↑ Souchelnytskyi S, Rönnstrand L, Heldin CH, ten Dijke P (2001). "Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases". Protein Kinase Protocols. Methods in Molecular Biology. Vol. 124. pp. 107–20. doi:10.1385/1-59259-059-4:107. ISBN   1-59259-059-4. PMID   11100470.
  11. 1 2 3 4 5 Massagué J, Chen YG (March 2000). "Controlling TGF-beta signaling". Genes & Development. 14 (6): 627–44. doi: 10.1101/gad.14.6.627 . PMID   10733523. S2CID   84047115.
  12. ↑ Ulloa L, Tabibzadeh S (June 2001). "Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor". The Journal of Biological Chemistry. 276 (24): 21397–404. doi: 10.1074/jbc.M010783200 . PMID   11278746.
  13. ↑ Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, et al. (July 2002). "Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542". Molecular Pharmacology. 62 (1): 58–64. doi:10.1124/mol.62.1.58. PMID   12065755. S2CID   792324.
  14. ↑ Blobe GC, Liu X, Fang SJ, How T, Lodish HF (October 2001). "A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC". The Journal of Biological Chemistry. 276 (43): 39608–17. doi: 10.1074/jbc.M106831200 . PMID   11546783.
  15. ↑ Online Mendelian Inheritance in Man (OMIM): TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE III; TGFBR3 - 600742
  16. ↑ Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (August 2001). "Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads". The EMBO Journal. 20 (15): 4132–42. doi:10.1093/emboj/20.15.4132. PMC   149146 . PMID   11483516.
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