A. Schematic representation of TGF-β family pathway activation
and action. Dimeric ligand binding induces assembly of two type I- and two type
II-receptors into a hexameric signaling complex, allowing the type II receptors
to activate the type I receptors by phosphorylation. The active type I receptors
in turn phosphorylate R-SMADs, which then form trimeric complexes with SMAD4,
translocate to the nucleus and regulate gene expression. R-SMADs are divided in
two functionally different branches, the SMAD1/5/8 branch (a.k.a. “the
BMP-pathway”), and the SMAD2/3 branch (a.k.a. “the
Activin/TGF-β-pathway”). Ligands on the left side are colored
blue, on the right side they are colored green to represent their pathway
selectivity. Downstream gene regulation, therefore, depends on which type I
receptor forms part of the active signaling complexes. B. The
TGF-β/activin and the BMP subfamilies each share a subset of type I
receptors and downstream effector SMADs. Notably, the family has over 33 ligand
genes in humans but only five type II and seven type I receptors, indicating
that there is substantial overlap in receptor utilization.