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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 108

they activate transcription (Module 2: Figure Smad sig- nalling pathway. One of its actions is to increase the tran-
nalling). scription of the p15 INK4B gene that codes for p15, which is
one of the cyclin-dependent kinase (CDK) inhibitors that
Smad activation of transcription inhibits cyclin D/cyclin-dependent kinase 4 (CDK4) com-
The receptor-regulated Smads (R-Smads) function as tran- plex that is one of the early events of the cell cycle signalling
scription factors responsible for activating a large num- cascade (Module 9: Figure cell cycle signalling mechan-
ber of target genes. Once they have been activated by the isms). Another important action is to repress c-Myc,which
cell-surface receptors, the activated Smads translocate into is one of the major transcriptional activators of genes that
the nucleus (Module 2: Figure Smad signalling). Some of function in cell proliferation. Such an inhibition of Myc
the ligands, such as transforming growth factor β (TGF- occurs during skin development when Smad2/3 induces
β), activin and Nodal activate receptors that are coupled the transcription of the Myc repressors Mad1 and Ovol1
to Smad2 and Smad3, whereas bone morphogenetic pro- to inhibit keratinocyte proliferation.
tein (BMP) acts through Smad1, Smad5 or Smad8. Once TGF-β plays an important role in regulating the pro-
these Smads have been phosphorylated on their C-terminal liferation of mesangial cells (Module 7: Figure mesangial
SSXS motif (Module 2: Figure TGF-βR activation)they cells). It also regulates the proliferation of stem cells such
leave the receptor, where they combine with Smad4 to form as the skeletal muscle satellite cells (Module 8: Figure Satel-
a dimer that then translocates into the nucleus (Module 2: lite cell activation)and the epidermal stem cells (Module
Figure Smad signalling). Once the dimer enters the nuc- 8: Figure epidermal stem cell).
leus, it recognizes and binds to a specific DNA motif. Smad2and 4are tumour suppressors. A germline muta-
The transcriptional activity of the Smads is facilitated tion in Smad4 has been linked to juvenile polyposis syn-
by associating with other site-specific transcription factors dromes (JPSs).
(TFs). Their activity is also modulated by coactivators and
repressors. For example, Smad4 binds directly to the co-
activator p300, which has an important role in activat- Wnt signalling pathways
ing transcription. The pathway on the right, which car- The Wnt signalling pathways play a critical role in the
ries out the action of receptors that bind ligands such as control of cell proliferation, cell fate specification and dif-
bone morphogenetic protein (BMP), use Smad1, 5 or 8 to ferentiation. These different pathways are activated by ex-
transmit information into the nucleus. As for the pathway tracellular lipoprotein signalling molecules called Wnts re-
described above, Smad4 is again used as a partner for the sponsible for transmitting information between cells over
translocation process, and the transcriptional processes are relatively short distances. There are three main pathways:
also similar. the canonical and two non-canonical pathways (Module 2:
The Smads stimulate transcription of the collagen type I Figure Wnt signalling pathways).
during the fibrogenesis induced in activated hepatic stellate The primary function of the canonical Wnt/β-catenin
cells in the liver (Module 7: Figure hepatic stellate cell). pathway is to activate gene transcription to control pro-
cesses during both development and in the adult organism.
Modulation of Smad signalling The functions of the non-canonical Wnt pathways are still
There are a number of ways that the Smad signalling path- somewhat of an enigma, since their precise functions have
way can be modulated. One mechanism is by an increase not been clearly identified, but there are clear indications
in the expression of inhibitory Smads (I-Smads), which that they may function in planar cell polarity (PCP).The
target the cell-surface receptors for degradation. This pro- Wnt/planar cell polarity (PCP) pathway, which has been
cess is mediated by the Smad ubiquitin-regulatory factors characterized in Drosophila, appears to act through various
(Smurfs), which are a family of ubiquitin E3 ligases that GTP-binding proteins. A closely related Wnt/Ca 2 + sig-
bind to the PY motif on the linker region of I-Smads nalling pathway, which has been described in vertebrates,
(Module 2: Figure Smad domain structure). The E3 ligase has a number of similar signalling components but also has
functions in the ubiquitin-proteasome system (Module 1: additional features such as the hydrolysis of PtdIns4,5P 2 to
Figure ubiquitin-proteasome system). activate signalling through InsP 3 /Ca 2 + and diacylglycerol
The mitogen-activated protein kinase (MAPK) sig- (DAG)/protein kinase C (PKC).
nalling pathway can also modulate Smad signalling by
phosphorylating sites located in the linker regions of Wnts
Smad1and 2(Module 2: Figure Smad domain structure). The term Wnt results from the fusion of the names of
This is an example of signalling cross-talk in that it provides two orthologous genes, the Drosophila segment polarity
a mechanism for the tyrosine kinase-linked receptors to gene Wingless (Wg) and a mouse proto-oncogene Int-1.
antagonize the action of the transforming growth factor β The human genome has 19 Wnt genes, many of which
(TGF-β) superfamily. appear to have distinct functions. They contain numer-
ous cysteine residues, one of which is palmitoylated, thus
Transforming growth factor β (TGF-β) inhibition making the Wnts somewhat insoluble, which may help to
of cell proliferation explain why they are short-range ligands. A large number
One of the major functions of transforming growth factor of Wnt-binding proteins, such as secreted frizzled-related
β (TGF-β) is to inhibit cell proliferation by altering ex- protein (SFRP) and Wnt inhibitory factor (WIF) also re-
pression of some of the key regulators of the cell cycle sig- strict their sphere of influence by acting as Wnt buffers.

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