Page 62 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 62

kinase (previously called PDK2) phosphorylates Ser-473. • It contributes to Myc degradation.
The activated PKB then functions to stimulate a variety • It phosphorylates the neuron-specific microtubule-
of molecular targets, including glycogen synthase kinase-3 associated protein tau, which forms tangles in neurons
(GSK-3) (which mediates the effect of insulin on glycogen during the onset of Alzheimer’s disease (Module 12:
metabolism) and the pro-apoptotic factor Bad. PKB also Figure amyloid plaques and tangles).
plays a role in redox signalling in apoptosis. • It plays a significant role in cardiac gene transcription,
PKB is a key player in cell growth control,where it where it has an important role in the NFAT shuttle
functions by phosphorylating tuberous sclerosis 1 and 2 (Module 12: Figure hypertrophy signalling mechan-
(TSC1/2), which integrate a number of inputs that control isms).
the activity of the target of rapamycin (TOR) (Module • GSK-3 activity can be regulated by disrupted in schizo-
9: Figure target of rapamycin signalling). PKB can also phrenia 1 (DISC1), which is mutated in some patients
translocate into the nucleus, where it phosphorylates the with schizophrenia. When mutated, DISC1 alters both
Forkhead box O (FOXO) transcription factors (Module 4: the structure and function of fast-spiking interneurons
Figure FOXO control mechanisms) that play an important (Module 12: Figure schizophrenia).
role in regulating the cell cycle.
A reduction in PKB activity by various mechanisms
Tec tyrosine kinase family
seems to be responsible for the onset in insulin resistance
All members of this tyrosine kinase family are cytoso-
(Module 12: Figure insulin resistance).
lic, but they translocate rapidly to the membrane through
pleckstrin homology (PH) domains that are particularly
Ribosomal S6 protein kinase 1 (S6K1)
sensitive to PtdIns3,4,5P 3 . A prominent member of this
This kinase plays an important role in regulating protein
family is Bruton’s tyrosine kinase (Btk). Once bound to
synthesis by phosphorylating the S6 ribosomal protein
the membrane, these enzymes are also phosphorylated by
(a component of the 40S ribosomal subunit), which then
Src family tyrosine kinases such as Lyn and Src. Activa-
enhances the translation of those mRNA transcripts that tion thus requires both translocation to the membrane and
contain a polypyrimidine tract at the 5’ transcriptional start phosphorylation on tyrosine residues. One of the func-
site. The control of S6K1 is complex in that it depends upon tions of these Tec tyrosine kinases is to enhance Ca 2 + sig-
a priming step that is followed by series of phosphoryla-
nalling by maintaining the activity of phospholipase Cγ
tion events at multiple sites that are sensitive to a number of (PLCγ). This enhancement of PLCγ activity by the Tec
kinases. The priming step depends on Ca 2 + , which appears kinases represents a major point of interaction between the
to act by opening up the enzyme so that it becomes sensit- inositol 1,4,5-trisphosphate (InsP 3 )/Ca 2 + signalling cas-
ive to phosphorylation by different kinases. One of these is sette and the PtdIns 3-kinase signalling cassette.
phosphoinositide-dependent kinase 1 (PDK1), which car-
ries out the wortmannin-sensitive phosphorylation. In ad- Bruton’s tyrosine kinase (Btk)
dition there are rapamycin-sensitive sites phosphorylated Bruton’s tyrosine kinase (Btk) is one of the non-receptor
by the target of rapamycin (TOR) (Module 9: Figure target protein tyrosine kinases (Module 1: Figure non-receptor
of rapamycin signalling). tyrosine kinases) that plays an important role in B cells
where it functions to activate PLCγ2(Module 9: Figure B
Glycogen synthase kinase-3 (GSK-3) cell activation). It has a similar mode of action in the mast
One of the primary functions of insulin is to act through cell FcεRI signalling pathway (Step 7 in Module 11: Figure
glycogen synthase kinase-3 (GSK-3) to stimulate the con- FcεRI mast cell signalling).
version of glucose into glycogen by increasing the activity Inactivation of Btk results in Bruton’s type X-linked
of glycogen synthase (Module 7: Figure skeletal muscle agammaglobulinaemia.
E-C coupling). GSK-3 is a proline-directed protein kinase
that usually requires a priming kinase to add a phosphate Inducible T cell kinase (Itk)
to its substrate before it can carry out further phosphoryla- As for Bruton’s tyrosine kinase (Btk) in B cells, inducible
tions. Casein kinase I (CKI) often acts as the priming kinase T cell kinase (Itk) has a similar function in controlling
as it does for β-catenin in the Wnt signalling pathway the maturation of T cells by activating phospholipase Cγ1
(Module 2: Figure Wnt canonical pathway). (PLCγ1) (Module 9: Figure TCR signalling).
GSK-3 also has a number of other signalling func-
tions:
Insulin receptor
• It phosphorylates nuclear factor of activated T cells Insulin has a major role to play in regulating a variety of
(NFAT) and thus contributes to the NFAT shuttle cellular processes, with particular emphasis on the regula-
(Module 4: Figure NFAT activation). tion of energy uptake and storage. The action of insulin is
• It contributes to the Wnt signalling pathway (Module carried out by the insulin receptor, which is a disulphide-
2: Figure Wnt canonical pathway). linked homodimer that belongs to the large family of re-
• It functions in dorsoventral specification during devel- ceptors that have tyrosine kinase domains (Module 1: Fig-
opment (Module 8: Figure dorsoventral specification). ure tyrosine kinase-linked receptors). An important com-
• It is one of the kinases that phosphorylates the tran- ponent of the signal transduction mechanism used by the
scription factor p53 (Module 4: Figure p53 domains). insulin receptor is the insulin receptor substrate (IRS),

C 2012 Portland Press Limited www.cellsignallingbiology.org