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TGF
β
LIGANDS
-pleiotropic growth factorIt can control several distinct and seemingly unrelated phenotypic effects These include1.Growth control2.Arrest and proliferation3.Differentiation
Cell deathThese ligands – 
 – 
Are cytokines
 – 
encoded by 42 open readingframes in humans
 – 
characterised by sixconserved cysteine residues
 – 
consists of two sub-families(TGF
β
/activin subfamily andthe BMP (bonemorphogenetic protein)subfamily)
 – 
 There are 5 TGF
β
ligands(TGF
β
1, 2 and 3 expressedin mammalian cells)
 – 
Active form of TGF
β
is adimer (i.e. 2 units)
 – 
stabilised by hydrophobicinteractions
 – 
Strengthened by disulphidebonding between each unit.
 – 
Each monomer comprisesextended
β
-sheetsinterlocked by 3 conserveddisulphide bonds
 – 
 These form a structureknown as the “cysteine knot”
 – 
Dimers suggest a complexwith two of each type of receptor
TGF b Receptors
•
•
Receptors are protein kinases that phosphorylate serine/threonine kinases
•
2 types of receptors : I and II
•
 Type II receptors phosphorylate the Type I receptor
•
comprises 12 members
•
All 12 members are dedicated to TGF
β
/BMP signalling1.7 Type I receptors2.5 Type II receptors
•
Each receptor consists of approx500 amino acids1.N-terminal extracellularligand binding domain2.A transmembrane region3.C-terminal intracellularserine/threonine kinasedomain
•
binding of ligand to Type I and Type II receptors initiate signalling
•
Signal is then transduced throughSmad proteins
Type I Receptors
••
Contain GS Domain (TTSGSGSG sequence)
•
GS domain is phosphorylated by the Type II receptor
•
 Therefore need both type I and II for active signalling
•
Extensions/truncations to N- and C-termini do exist
•
.
 
SMAD
••
 There are 3 functional classes of Smad proteins1.Receptor-regulated Smad Proteins(R-Smads; Smads 1, 2, 3, 5 and 8)2.Co-mediator Smad protein (Co-Smad; Smad4))3.Inhibitory Smad proteins (I-Smad;Smads 6 and 7)
 
Mechanism of Ligand Binding
There are two distinct modes of ligand binding to the receptors.••BMPs
1.BMP ligands have a very highaffinity for the extra-cellularligand binding domain of thetype I receptors.2.Once bound the type I receptor-ligand complex has a a higheraffinity for binding to type IIreceptors than the ligand alone.3.Receptor-ligand interactions arepredominantly hydrophobic andinvolve a highly conservedphenylalanine residue in thereceptor
•
TGF
β
/Activin
1.They have a high affinity for type IIreceptors and2.They do not interact directly withtype I receptors on their own.3.They bind tightly to the type IIreceptor domain first.4.This binding then allows thesubsequent incorporation of thetype I receptor to form a largeligand-receptor complex.5.This involves ligand dimers and 4receptor molecules.6.Receptor-ligand interactions arepredominantly hydrophobic andinvolve a highly conservedphenylalanine residue in thereceptor.
•Ligand Receptor Interactions
 
 
Mechanism of Receptor Activation
•
•
Proximity of receptors in the complex facilitates the phosphorylation and activationof the type I receptor by the type II receptor.
•
 The kinase of the type II receptor phosphorylates multiple serine and threonineresidues in the TTSGSGSG sequence of the type I cytoplasmic GS region.
•
GS region serves as an important regulatory domain for TGF
β
signalling.
•
Phosphorylated TGF
β
-RI binds efficiently to Smad2
•
has enhanced phosphorylation specificity for the C-terminal serine residues
•
 The phosphorylated receptor cannot be recognised by its inhibitors
•
Therefore phosphorylation activates the receptor by switching the GSregion from a preferred binding surface for inhibitors into a binding surfacefor the R-Smad substrates
Regulation of Receptor Activation
•
•
Access of TGF
β
ligands to its receptors is controlled by two classes of molecules withopposite functions.1.One class act as ligand binding traps
•
 These prevent the ligand from accessing the membrane receptors
•
Ligand binding traps occupy the same hydrophobic pocket in the ligand that thereceptor requires for binding
•
 Therefore they block binding1.The second class acts as accessory receptors or co-receptors
•
 They promote ligand binding to the signalling receptors
•
 They have some selectivity in this role
•
 TGF
β
type III receptor (a proteoglycan) enhances signalling by mediating binding of growth factors to the TGF
β
-RII.
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