TGF beta signaling pathway

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing

Mechanism

Ligand binding

The TGF beta superfamily of ligands includes:

There are three activins:

nerve cell

survival factors.

The BMPs bind to the

cell differentiation

, anterior/posterior axis specification, growth, and homeostasis.

The TGFβ family includes:

TGF-beta receptor type-2

(TGFBR2).

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

paracrine signalling

.

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.

residues of the Type I receptor, which activates the protein.

SMAD phosphorylation

There are five receptor regulated SMADs:

) and HGS (Hepatocyte growth factor-regulated tyrosine kinase substrate).

SARA is present in an early

CoSMAD binding

The now phosphorylated RSMAD has high affinity for coSMAD (e.g.

) 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

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

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

of R-SMADs and receptors.

Ligand agonists/antagonists

Both

Members of the DAN family of proteins also antagonize TGF beta family members. They include

.

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

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

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

] 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 ligand	Ligand inhibitors	Type II Receptor	Type I receptor	R-SMADs	coSMAD	I-SMADs
Activin A	Follistatin	ACVR2A	ACVR1B (ALK4)	SMAD3	SMAD4	SMAD7
GDF1		ACVR2A	ACVR1B (ALK4)	SMAD3	SMAD4	SMAD7
GDF11		ACVR2B	TGFβRI (ALK5)	SMAD3	SMAD4	SMAD7
BMP2-8	DAN	BMPR2	BMPR1A (ALK3), BMPR1B (ALK6)	SMAD8	SMAD4	SMAD7
Nodal	Lefty	ACVR2B	ACVR1B (ALK4), ACVR1C (ALK7)	SMAD3	SMAD4	SMAD7
TGFβs	THBS1, Decorin	TGFβRII	TGFβRI (ALK5)	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

External links

• Kyoto Encyclopedia of Genes and Genomes -TGF beta signaling pathway
  map
• Netpath
  - A curated resource of signal transduction pathways in humans

References