Page 104 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 104

Module 2: Figure JAK/STAT function
Agonist

P P P P P P P P
JAK
P P P P P P
1 2
4
_
3
SH2 domain
STAT 5
DNA-binding P P
domain
SOCS
CRM1 Export Import Importin

8 6
Importin
CRM1
N-PTP Target genes
SOCS
P P 7

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) activation cascade.
A schematic summary of the main sequence of events responsible for the activation of signal transducers and activators of transcription (STATs).
Agonist activation of cell-surface receptors induces dimerization of receptor subunits, resulting in the stimulation of resident Janus kinases (JAKs). The
JAKs then carry out a sequential series of three phosphorylation reactions to activate the STATs, which then enter the nucleus to induce transcription.
The binding between STATs and DNA is shown in Module 2: Figure STAT1/DNA complex .

signalling pathways controlled by the TGF-β superfamily Ligands
have been associated with many cancers of epithelial and The Smad signalling pathway is activated by a number of
lymphoid origins, which fail to respond to the normal anti- closely related ligands. The flagship ligand is transforming
proliferative effects of TGF-β.The TGF-β receptor is one growth factor β (TGF-β), but there are a number of other
of the tumour suppressors that are switched off in many ligands such as activin and nodal that also act through the
cancers and particularly in colorectal cancer (CRC). Smads (Module 2: Table Smad signalling toolkit). Nodal
An increase in the expression of TGF-β1 may play a has a role to play in establishing left-right asymmetry in
critical role in the transition from stable hypertrophy to the developing embryo.
congestive heart failure (CHF).
Accessory receptors
Smad signalling toolkit
These are cell-surface receptors that function as co-
The Smad signalling pathway is made up from a large
receptors in that they promote the binding of the lig-
number of components (Module 2: Table Smad signalling
ands to their signalling receptors. For example, the access-
toolkit). Specific cell types express different combinations
ory receptor endoglin is essential for the action of activin
of these components so that there is considerable variab-
receptor-like kinase 1 (ALK1) during the activation of an-
ility in the nature of Smad signalling pathways. However,
giogenesis.
the overall organization is fairly similar and is best ex-
emplified by the action of transforming growth factor β
(TGF-β) itself. The different components of the toolkit TGF-β signalling receptors
have been grouped together on the basis of their function There are two groups of signalling receptors (Type I and II)
in the signalling pathway (Module 2: Table Smad signalling (Module 2: Table Smad signalling toolkit). These receptors
toolkit):
contain a single membrane-spanning region that separates
the extracellular ligand-binding domain from the cytoso-
Ligand traps lic region that contains a serine/threonine kinase domain.
These are a large group of proteins that control access The Type I receptor also contains a glycine/serine-rich
of the ligands to their cell-surface receptors. These ligand (GS) domain, which is phosphorylated by the Type II re-
traps can have an important inhibitory action since they ceptor during the signal transduction process (as occurs
can prevent the ligands from reaching their cell-surface during the response to TGF-β Module 2: Figure TGF-βR
receptors. For example, follistatin inhibits the action of activation). Ligands act to complex these receptors so that
activin on gonadotrophs (Module 10: Figure gonadotroph the Type II can then activate the Type I, which in turn
regulation). activates the Smads (Module 2: Figure Smad signalling).

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