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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 61

Module 2: Figure PtdIns 3-kinase signalling

Growth factor

PtdIns3,4,5P GPCR
PTKRs 3
Ras
P P Ras p101/
p110
P P p85 p110 p84
PtdIns- Class IB PtdIns-
4,5P P P Class IA 4,5P
2 PI 3-K 2
PI 3-K
PDK1/2 Rac
Rho Superoxide
formation
Cdc42
Btk PKB
Itk
Cytoskeletal
rearrangement
PLC
PKCs
S6K TOR BAD GSK3 FOXO
IP DAG
3
Protein Cell Glycogen Gene
Ca 2+ PKCs synthesis survival metabolism transcription

The PtdIns 3-kinase signalling pathway.
The precursor lipid PtdIns4,5P 2 is phosphorylated on the 3-position by Class I PtdIns 3-kinases (PtdIns 3-Ks) to generate the lipid second messenger
PtdIns3,4,5P 3 . The Class 1A enzyme has regulatory subunits such as p85 that attaches the catalytic p110 subunits to the phosphorylated tyrosine
residues on the cytoplasmic domains of activated growth factor receptors. The Class 1B enzymes (p110γ), which are activated by G protein-coupled
receptors (GPCRs), translocate to the membrane by binding to the Gβγ subunit. When brought into the vicinity of the membrane, these PtdIns 3-kinases
form the 3-phosphorylated lipid messenger PtdIns3,4,5P 3 , to regulate a large number of processes. It binds to other signalling components such
as Btk and PLCγ (shown in pink). It stimulates phosphoinositide-dependent kinase 1/2 (PDK1/2) and protein kinase B (PKB), which activate a large
number of downstream targets (yellow). It also activates monomeric G proteins (Rac, Rho and Cdc42) to stimulate both cytoskeletal rearrangement
−• ) formation (shown in green).
and superoxide radical (O 2

• PtdIns 3-kinase signalling in cardiac hypertrophy is an (PKB), which translocates to the membrane, where it binds
example where this signalling system carries out mul- to PtdIns3,4,5P 3 (Module 2: Figure PtdIns 3-kinase sig-
tiple roles in the same cell (i.e. inhibits apoptosis, ac- nalling). This binding alters the conformation of PKB so
tivates protein synthesis and facilitates a programme that critical sites become available to PDK1. Like PKB,
of foetal gene transcription (Module 12: Figure hyper- PDK1 has pleckstrin homology (PH) domains that also
trophy signalling mechanisms). bind to the 3-phosphorylated lipid messengers that serve
• Modulation of InsP 3 -induced Ca 2 + release by phos- to activate their kinase activity. PDK1 is also responsible
phorylation of the InsP 3 receptor, and this could provide for phosphorylating and activating other signalling mo-
a possible mechanism for the action of insulin in liver lecules such as ribosomal S6 protein kinase 1 (S6K1) and
cells (Module 7: Figure liver cell signalling). atypical protein kinase Cζ (PKCζ).
• PtdIns3,4,5P 3 activates the monomeric G proteins Rac
(Module 2: Figure Rac signalling), Rho (Module 2: Fig- Protein kinase B (PKB)
ure Rho signalling)and Cdc42(Module 2: Figure Cdc42 Protein kinase B (PKB), which is also known as Akt,
signalling). is a serine/threonine protein kinase that functions in
• Formation of osteoclast podosomes (Module 7: Figure the PtdIns 3-kinase signalling pathway (Module 2: Fig-
osteoclast podosomes). ure PtdIns 3-kinase signalling). PKB has three members
• Contributes to the amplification of the early polarity (PKBα,PKBβ and PKBγ) that are activated through a
signalling during neutrophil chemotaxis (Module 11:
two-stage process. Firstly, it translocates to the mem-
Figure neutrophil chemotactic signalling).
brane by binding to either PtdIns3,4P 2 or PtdIns3,4,5P 3
• Functions as a regulator of autophagy (Module 11: Fig- through pleckstrin homology (PH) domains. The latter
ure autophagy). appears to be particularly important when cells are stud-
ied in vivo. The next stage depends upon its interaction
Phosphoinositide-dependent kinase 1 (PDK1) with phosphoinositide-dependent kinase 1 (PDK1),which
One of the main functions of phosphoinositide-dependent then completes the activation process by phosphorylating
kinase 1 (PDK1) is to phosphorylate protein kinase B PKB on Thr-308. In addition, a DNA-dependent protein

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