Signal Processing in the TGF-β Superfamily Ligand-Receptor Network
Figure 3
Signaling and Trafficking in the TGF-β Pathway
Receptors in the plasma membrane interact with the signaling peptides of the TGF-β superfamily to form active complexes. Receptors and activated ligand-receptor complexes can internalize via clathrin-coated pits into endosomes, from where the active ligand-receptor complexes phosphorylate the cytoplasmic R-Smads (“receptor Smads,” either the Smad1/5/8 or the Smad2/3 group) [33].
The phosphorylated R-Smads form complexes with the Co-Smad (Smad4) and then translocate into the nucleus where they act as transcriptional regulators of about 300 target genes.
The internalized receptors recycle back to the plasma membrane (with a characteristic time of ~30 min) via a rab11-dependent, rab4-independent pathway [14]. After returning to the plasma membrane, the receptors that were actively signaling can be targeted for degradation or be used for further ligand-binding or internalization [14]. Receptors that did not bind ligands are simply returned to the plasma membrane. As a consequence of the trafficking processes, only about 5%–10% of receptors are present in the plasma membrane [15].
In addition to the traditional clathrin pathway, active ligand-receptor complexes can recruit Smad7-Smurf2 [28], which then targets them to lipid raft–caveolar compartments (right) for degradation [15].
The ligands do not return back to the plasma membrane, but disassociate from the receptors before recycling and undergo direct degradation via the lysosomes [14].
Note that, in addition to the ligand-induced receptor degradation, we also consider a receptor degradation pathway that functions independently of ligand-binding; this represents a “constitutive” or ligand-independent degradation pathway (left).