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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 105

Module 2: Table Smad signalling toolkit Module 2 Table continued
Components of the Smad signalling toolkit. Component Comment
Component Comment Receptor-regulated Smads
Ligand traps (R-Smads)
LAP Latency-associated polypeptide Smad1
that binds TGF-β Smad2
Decorin Binds TGF-β Smad3
α 2 -Macroglobulin Binds TGF-β Smad5
Noggin Binds to BMPs (Module 8: Figure Smad8
epidermal stem cell) Co-mediator Smad
Follistatin Binds to activins and BMPs. It (Co-Smad)
inhibits activin action on Smad4 A germ-line mutation in Smad4 has
gonadotrophs (Module 10: been linked to juvenile polyposis
Figure gonadotroph regulation) syndromes (JPSs).
Chordin/SOG Binds to BMPs Inhibitory Smads (I-Smad)
DAN/Cerberus Binds to BMPs Smad6
Smad7
Ligands
TGF-β1 Transforming growth factor β Smad regulatory factors
(Module 1: Figure enzyme-linked SARA Smad anchor for receptor activation
receptors) Smurf1 Smad ubiquitin-regulatory factor 1.
TGF-β2 Smirf1 also regulates the
TGF-β3 degradation of Rho during
Activin One of its functions is to increase neutrophil chemotaxis (Module
the transcription of FSH in 11: Figure neutrophil
gonadotrophs (Module 10: chemotactic signalling)
Figure gonadotroph regulation) Smurf2 Smad ubiquitin-regulatory factor 2
Myostatin Growth and differentiation factor 8
(GDF8) (see Module 8: Figure
satellite cell activation)
Nodal The activin receptor-like kinase 1 (ALK1), which re-
BMP Bone morphogenetic factor sponds to TGF-β, is strongly expressed in endothelial cells
functions in the control of
epidermal stem cells (Module 8: where it functions in the formation of blood vessels. Loss-
Figure epidermal stem cell), in-function mutations in the ACVRL1 gene have been
proliferation of SNO cells linked to hemorrhagic telangiectasia-2 (HHT2).
(Module 8: Figure HSC
regulation) and differentiation of
white fat cells (Module 8: Figure Smads
white fat cell differentiation)
Inhibin Inhibits activin action in The Smads are the intracellular transducers of the Smad
gonadotrophs (Module 10: signalling pathway. There are three Smad types. Receptor-
Figure gonadotroph regulation) regulated Smads (R-Smads), which are activated by the
Accessory receptors signalling receptors, carry information into the nucleus. A
Betaglycan Facilitates the binding of TGF-β to single co-mediator Smad (Co-Smad) acts together with the
the Type II receptors. Mediates
the action of inhibins in R-Smads. Inhibitory Smads (I-Smads) set up a negative-
gonadotrophs (Module 10: feedback loop to limit the activity of the R-Smads. These
Figure gonadotroph regulation) different activities are reflected in the domain structure of
Cripto
Endoglin This accessory receptor is essential the Smad family.
for the action of ALK1 during the
activation of angiogenesis
Smad regulatory factors
Signalling receptors There are a number of proteins that contribute to the Smad
Type I receptors
ALK1 Activin receptor-like kinase 1 is also signalling pathway.
known as ACVRL1 (activin
receptor-like 1) expressed mainly
in endothelial cells Domain structure of the Smad family
ALK2 Activin receptor-like kinase 2 is also The main structural feature of the Smads are the two MAD
known as activin A receptor type homology domains (MH1 and MH2) that function both
1 (ACVR1), usually responds to
BMP in the protein--protein and protein--DNA interactions that
ALK3 Activin receptor-like 3 occur during the process of signal transduction (Module
ALK4 Activin receptor-like 4 2: Figure Smad domain structure). The regulatory Smads
ALK5 Activin receptor-like kinase 5 is also
known as TGFβ type I (TβRI) also have a C-terminal SSXS motif, which is critical for the
ALK6 Activin receptor-like 6 transduction process because two of the serine residues are
ALK7 Activin receptor-like 7 phosphorylated by the type I receptors as part of the Smad
ACVRI Activin receptor type I (ACVRI)
Type II receptors signalling mechanism. There also are numerous other sites
ACVRIIA Activin receptor type IIA binds to that are phosphorylated by various kinases from other
activin and interacts with activin signalling pathways. The linker region between the MH1
receptor type I (ACVRI)
ACVRIIB and MH2 domains contains a phosphotyrosine (PY) mo-
BMPRII tif, which is an interaction site for the binding of the Smad
TβRII ubiquitin-regulatory factors 1 and 2 (Smurf1/2), which is
an ubiquitin ligase that controls the selective proteolysis

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