TGF beta signaling pathway

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The Transforming growth factor (TGF) signaling pathway is involved in many cellular processes including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular processes that the TGF beta signaling pathway is involved in, the process is relatively simple. A TGF beta ligand binds to a type II receptor which recruits and phosphorylates a type I receptor. The type I receptor phosphorylates a receptor regulated SMAD (R-SMAD) which binds a coSMAD and enters the nucleus where it helps to form a transcription factor.

Contents 1 Mechanism 1.1 Ligand Binding 1.2 Receptor recruitment and phosphorylation 1.3 SMAD phosphorylation 1.4 CoSMAD binding 1.5 Transcription 2 Pathway regulation 2.1 Ligand agonists/antagonists 2.2 Receptor regulation 2.2.1 R-SMAD ubiquitination 3 Summary table 4 External links 5 References

[edit] Mechanism

[edit] Ligand Binding

The TGF Beta superfamily of ligands include: Bone morphogenetic proteins, Anti-müllerian hormone (AMH), Activin, Nodal and TGF beta's^[1]. 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 catalyses the phosphorylation of the Type I receptor. Each class of ligand binds to a specific type II receptor^[2].In mammals there are seven known type II receptors and five type I receptors^[3].

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

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, dorsa-ventral specification, growth, and homeostasis.

The TGF beta family include: TGFβ1, TGFβ2, TGFβ3. Like the BMPS, TGF betas are involved in embryogenesis and cell differentiation, but they are also involved in apoptosis, as well as 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)^[3].

[edit] Receptor recruitment and phosphorylation

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^[4]. 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 SG domain of the type I receptor consists of a series of about thirty serine-glycine repeats^[5]. The binding of a TGF beta 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.

[edit] SMAD phosphorylation

There are five receptor regulated SMADs: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD9. There are essentially two intracellular pathways involving these R-SMADs. TGF beta's, Activins and Nodals are mediated by SMAD2 and SMAD3, while BMPs, GDFs and AMH 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 TGF beta 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^[6]. SARA recruits an R-SMAD. SARA permits the binding of the R-SMAD to the L45 region of the Type I receptor^[7]. 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^[8].

[edit] CoSMAD binding

The phosphorylated RSMAD has a high affinity for a coSMAD (eg. SMAD4) and forms a complex with one.

[edit] Transcription

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.

TGF betas cause the transcription of mRNAs involved in apoptosis, extracellular matrix neogenesis and immunosuppression. It is 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, and mesoderm and endoderm induction.

[edit] 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 that the pathway is modulated both positively and negatively: There are agonists for ligands and R-SMADs; there are decoy receptors; and R-SMADs and receptors are ubiquitinated.

[edit] Ligand agonists/antagonists

Both chordin and noggin are antagonists of BMP's. They bind BMP's preventing the binding of the ligand to the receptor. It has been demonstated 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^[9].

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 briges. 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^[9].

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 asymetrically 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^[10].

[edit] Receptor regulation

The Transforming growth factor receptor 3 (TGFBR3) is the most abundant of the TGF-β receptors yet^[11], it has no known signaling domain^[12]. It however may serve to enhance the binding of TGF beta ligands to TGF beta 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^[9].

Bone and Activin membrane bound inhibitor (BAMBI), has a similar extracellular domain as type I receptors. It lacks an intracellular serine/threonine protine 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 TGF beta signaling and may limit tgf-beta expression during embryogeneis. It requires BMP signaling for its expression^[9]. It resides in the nucleus and upon TGF beta 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 TGF beta signaling suggesting that they are downstream targets of TGF-beta signaling.

[edit] R-SMAD ubiquitination

The E3 ubiquitin-protein ligases SMURF1 and SMURF2 regulate the levels of SMADs. They accept ubiquitin from a 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 enhances the inhibitory action of SMAD7 while reducing the transcriptional activities of SMAD2.

[edit] Summary table

TGF Beta superfamily ligand	Type II Receptor	Type I receptor	R-SMADs	coSMAD	Ligand inhibitors
Activin A	ACVR2A	ACVR1B (ALK4)	SMAD2 , SMAD3	SMAD4	Follistatin
GDF1	ACVR2A	ACVR1B (ALK4)	SMAD2 , SMAD3	SMAD4
GDF11	ACVR2B	ACVR1B (ALK4)	SMAD2 , SMAD3	SMAD4
Bone morphogenetic proteins	BMPR2	BMPR1A (ALK3), BMPR1B (ALK6)	SMAD1 SMAD5, SMAD9	SMAD4	Noggin Chordin, DAN
Nodal	ACVR2B	ACVR1B (ALK4), ACVR1C (ALK7)	SMAD2 , SMAD3	SMAD4	Activin, Lefty
TGFβs	TGFβRII	TGFβRI (ALK5)	SMAD2 , SMAD3	SMAD4	LTBP1, THBS1, Decorin

[edit] External links

• Kyoto Encyclopedia of Genes and Genomes -TGF beta signaling pathway map

[edit] References

1. ^ Prostite Documentation PDOC00223. Retrieved on 2006-07-01.
2. ^ Alberts, Bruce, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter (2002). Molecular Biology of the Cell. New York, NY: Garland Science. ISBN 0-8153-3218-1.
3. ^ ^{a b} Munir, S., Xu G,Wu Y, Yang B, Lala PK, Peng C. (Jul 2004). "Nodal and ALK7 Inhibit Proliferation and Induce Apoptosis in Human Trophoblast Cells". J Biol Chem. 279. Retrieved on 2006-07-02.
4. ^ Wrana, JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massague J. (Dec 1992). "TGF beta signals through a heteromeric protein kinase receptor complex. ". Cell 71. Entrez PubMed 1333888.
5. ^ Pfam entry TGF_beta_GS. Retrieved on 2006-07-01.
6. ^ (Mar 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.". J Biol Chem. 4: 280. Entrez PubMed 15613484.
7. ^ Moustakas, A. (Sep 2002). "Smad signalling network.". J Cell Sci. 115. Entrez PubMed 12154066. Retrieved on 2006-07-01.
8. ^ Souchelnytskyi, S., Ronnstrand, L; Heldin, CH; ten Dijke, P. "Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases". Methods Mol Biol 124. Entrez PubMed 11100470.
9. ^ ^{a b c d} Massague, J, Chen YG. (Mar 2000). "Controlling TGF-beta signaling.". Genes Dev. 14. Entrez PubMed 10733523. Retrieved on 2006-07-01.
10. ^ Ulloa, Luis, Siamak Tabibzade (Jun 2001). "Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta receptor". J Biol Chem. 276. Retrieved on 2006-07-02.
11. ^ Blobe, GC, Liu X, Fang SJ, How T, Lodish HF. (Oct 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". J Biol Chem. 276. Retrieved on 2006-07-02.
12. ^ TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE III; TGFBR3. pubmed. Retrieved on 2006-07-01.

Cell signaling
Key concepts    - Ligand | Receptor | Second messenger | Protein kinase | Transcription factor | Cell signaling networks
Pathways    - Apoptosis | Ca2+ signaling | Cytokine signaling | Hedgehog | Integrin signaling | JAK/STAT | Lipid signaling | MAPK/ERK pathway | mTOR | NF-kB | Notch | p53 | TGFβ | Wnt