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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 106

Module 2: Figure Smad domain structure

Type I receptor
Smurf1/2
binding phosphorylation sites
PY P P
MH1 MH2 --SSXS- R-Smads
(Smad1,2,3,5,8)
NLS

MH1 MH2 Co-Smad
(Smad4)
NLS NES
Smurf1/2
binding
PY
MH2 I-Smads
(Smad6,7)

MAPK phosphorylation sites
CaMKII phosphorylation sites
PKC phosphorylation sites

The domain structure of the three Smad family members.
The receptor-regulated Smads (R-Smads) have a MAD homology domain 1 (MH1) in the N-terminal region and an MH2 in the C-terminal region.
These two domains play a critical role in carrying out the protein--protein and protein--DNA interactions. A nuclear localization signal (NLS) is located
within MH1 and functions in the transport of the R-Smads into the nucleus. The SSXS motif at the C-terminus contains the two serine residues that
are phosphorylated by the Type I receptors during the process of signal transduction (Module 2: Figure TGF-βR activation).

of the Smads. The single co-mediator Smad (Co-Smad, i.e. the following steps shown in Module 2: Figure TGF-βR
Smad4) resembles the R-Smads in some aspects. It also has activation.
MH1 and MH2 domains, but here the latter is split. In ad-
dition to the NLS, it also has a nuclear export signal (NES).
Smad4 lacks the C-terminal phosphorylation motif, but it 1. The ligand, in this case TGF-β, is often held in a latent
does contain a number of phosphorylation sites. The two ligand complex by being bound to one of the ligand trap
inhibitory Smads (I-Smads) lack an MH1 domain, but they proteins such as latency-associated polypeptide (LAP)
have the Smurf1/2-binding PY motif. or decorin. When it dissociates from the ligand trap, it
can be taken up by one of the accessory receptors such
as betaglycan.
Smad signalling mechanism 2. The TGF-β then associates with the two TGF-β re-
The Smad signalling mechanism can be divided into two ceptor components to assemble an agonist/receptor
parts. Firstly, there is the process of transforming growth complex. In the absence of ligand, the Type I and II
factor β (TGF-β) receptor activation, which concerns the receptor components exist as homodimers which are
way in which ligands such as TGF-β interact with the then brought together by TGF-β.
signalling receptors to trigger Smad activation (Module 3. When the two receptor types have been complexed
2: Figure TGF-βR activation). The critical aspects of this by TGF-β, the serine/threonine kinase domain on the
activation process are the phosphorylation reactions that Type II receptors phosphorylates the serine residues
occur within the receptor complex. The Type II recept- on the glycine/serine-rich (GS) region of the Type I
ors are constitutively active and phosphorylate the Type receptors.
I receptors. These activated Type I receptors then act to 4. These phosphorylated GS regions on the Type I re-
phosphorylate the Smads. ceptors provide a docking site for the MAD homology
The second part is the Smad activation of transcrip- domain 1 (MH1) domain of Smad2 or Smad3. This re-
tion, during which the phosphorylated receptor-regulated cruitment of the Smads to the membrane is facilitated
Smads (R-Smads), together with their partner Smad4, by Smad anchor for receptor activation (SARA). Once
translocate into the nucleus to induce gene transcription attached to the receptor, the SSXS motif is brought into
(Module 2: Figure Smad signalling). contact with the serine/threonine kinase domain, and
two of the serine residues are phosphorylated.
Transforming growth factor β (TGF-β) receptor 5. Once Smad2/3 have been phosphorylated, their affinity
activation for both the receptor complex and for SARA is reduced,
Activation of the transforming growth factor β (TGF-β) and the two proteins pass into the cytoplasm. The ac-
receptor depends upon a series of reactions as illustrated by tivated Smads then translocate into the nucleus where

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