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TGF (TUMOUR GROWTH FACTOR)

TGF (TUMOUR GROWTH FACTOR)

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Categories:Types, Research, Science
Published by: priyaa on Oct 25, 2009
Copyright:Attribution Non-commercial

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11/07/2012

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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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