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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 74

Module 2: Figure sites of ROS formation

Agonist

NADPH oxidase
complex on the
plasma membrane
NADH
ROS
NAD +

ROS
Leakage of electrons
from mitochondrial
electron transport
O
2 chain

H O
2

The two main sites of reactive oxygen species (ROS) formation.
There are two main sites of ROS formation in cells. One is at the level of the plasma membrane, where an NADPH oxidase complex is activated by
cell signalling pathways. The other is at the mitochondria, where ROS are produced as a result of electron leakage from the electron transport chain.
As indicated, this production of ROS appears as microdomains indicating that ROS signalling might be highly localized in cells.

Module 2: Figure plasma membrane ROS formation

Growth
Cytokines factors Hormones

NADPH
oxidase

PIP PI 3-K PIP Rac
2 3 Cyt b NADPH
+
NADP
PTEN
O
2 O
2
PIP
2 Superoxide
- dismutase
Tyrosine
phosphatase
H 2 O 2
Channel
modulation
Oxidation
SH S Gene
S transcription
SH
Reduction
Apoptosis

Receptor-dependent reactive oxygen species (ROS) formation at the plasma membrane.
The formation of reactive oxygen species (ROS) occurs in response to many external signals such as cytokines, growth factors and hormones. In
many cases, these signals activate receptors coupled to PtdIns 3-kinase (PI 3-K) which produces PtdIns3,4,5P 3 (PIP 3 ) that then acts through Rac
to stimulate NADPH oxidase at the plasma membrane. An electron is removed from NADPH and transferred to oxygen to form superoxide radical
−• −• is then transformed by the addition of further electrons by superoxide dismutase (SOD) to form hydrogen peroxide (H 2 O 2 ). There
(O 2 ). This O 2
is a positive-feedback loop that will amplify the redox signalling pathway because one of the actions of H 2 O 2 is to inhibit the enzyme phosphatase
and tensin homologue deleted on chromosome 10 (PTEN) that hydrolyses PIP 3 .

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