Biology Reference
In-Depth Information
TGF-
β
family ligand
Type IIR
Heterotetrameric complex
I/II-II/I
RI-P
R-Smad-P
Smad4
R-Smad/Smad4
+
DNA binding co-factors
+
Co-activator/co-repressors
Responsive target genes
Figure 7.1
A flowchart of the TGF-β signalling cascade leading to the formation of Smad
transcription factors (Sherbet, 2011a).
and pharmacokinetics of single-dose infusions. The antibody is well tolerated but
preliminary findings have revealed some side effects (Trachtman et al., 2011). A
study of systemic sclerosis is under way at present to assess the effects of the anti-
body on the skin of patients (NCT01284322). Relevant in the present context are two
studies that began in 2011. One of them relates to the safety and effects on possible
tumour regression of combining radiotherapy and Fresolimumab administration to
patients with metastatic breast cancer (NCT01401062). The second one is a phase II
study of malignant glioma (NCT01472731).
Small Molecule Inhibitors of the TGF-
β
Receptor Family
TGF-β family of ligands transduce their signals via the type I and type II (RI and
RII) receptors and type III accessory or co-receptors. These transmembrane recep-
tors consist of an extracellular ligand-binding domain, a transmembrane domain
and a cytoplasmic serine/threonine kinase domain. Seven type I ALK and five type
II receptors have been identified. Upon ligand binding, the type II receptor initially
engages type I to form a heterotetramer receptor complex, which phosphorylates and
activates type I (I-P*). The activated type I receptor in turn phosphorylates cytoplas-
mic R-Smads. These bind to Smad4. The R-Smad-P*/Smad4 complex now within
the nucleus integrates with co-factors leading to the recruitment of transcription co-
activators or co-repressors (
Figure 7.1
) (Sherbet, 2011a).
Inhibition of TGF-β RTKs has been tested in dermal sclerosis. Blocking TGF-β
RI ALK-5 using LY36494 (
SD208
) has been shown to suppress expression of type I
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