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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 63

Module 2: Figure insulin receptor

1
Cysteine-rich domain
L1
Fibronectin III repeat

L2 Insulin Tyrosine kinase domain

SS SS SS SS
SS SS
PtdIns4,5P PtdIns3,4,5P
2 3
972 5
P P IRS
P p85
1158 P P P P
1162 P P PI 3-K
1163 P 2 P
PDK1/2
3
1328 6
1334 P P P 4
P
PKB
IRS Glycogen Glucose
synthesis entry
p85 Lipid Protein
PI 3-K synthesis synthesis

Activation of the PtdIns 3-kinase signalling pathway by the insulin receptor.
The insulin receptor is a homodimer that is connected together by disulphide bonds. Each monomer consists of an α-chain, which is extracellular
and has the insulin-binding region. The β-chain has a single membrane-spanning region with a large intracellular region that contains the tyrosine
kinase domain that is critical for the process of signal transduction that proceeds through a sequence of events as described in the text.

which is a classical scaffolding protein (Module 6: Figure • It stimulates glucose uptake and glycogen synthesis
IRS domain structure). in skeletal muscle cells (Module 7: Figure skeletal
The function of the insulin receptor depends upon the muscle E-C coupling).
activation of the PtdIns 3-kinase signalling pathway that • It stimulates glycogen synthesis in liver cells (Module
occurs through the sequence of events shown in Module 7: Figure liver cell signalling).
2: Figure insulin receptor:
The onset of diabetes (i.e. Type 2 diabetes) begins when
cells become resistant to the action of insulin in energy
uptake and storage.
1. Insulin binds to the extracellular domain to induce a
conformational change in the receptor resulting in the
activation of the intracellular tyrosine kinase domains. PtdIns3,5P 2 signalling cassette
2. Once activated, the tyrosine kinase domains undergo The PtdIns3,5P 2 signalling cassette functions in membrane
autophosphorylation whereby they phosphorylate up and protein trafficking and particularly in the events that
to six tyrosine residues on the opposite β chain. occur during the early endosome maturation to lysosome
3. The insulin receptor substrate (IRS), which is a scaf- (see step 10 in Module 4: Figure membrane and pro-
folding domain (Module 6: Figure IRS domain struc- tein trafficking). The early endosome is rich in PtdIns3P
ture), attaches itself to juxtamembrane phosphotyr- that is converted into PtdIns3,5P 2 (Module 2: Figure loc-
osine residue 972. Once it is drawn into the vicinity alized inositol lipid signalling), which then orchestrates
of the receptor, the tyrosine kinase domain also phos- the trafficking events responsible for the transformation
phorylates IRS on multiple residues. of the early endosome into the multivesicular endosome
4. The phosphotyrosine residues on IRS then function as (MVE) that end up as lysosomes. The PtdIns3,5P 2 seems
docking sites for Class IA PtdIns 3-kinase (PI 3-K). to act by stimulating TRPML1 channels to create the
5. The PI 3-K then phosphorylates PtdIns4,5P 2 to form local domains of Ca 2 + necessary to activate the endo-
the lipid second messenger PtdIns3,4,5P 3 . some fusion to form the lysosomes. The formation of
6. The PtdIns3,4,5P 3 then activates the PtdIns 3-kinase PtdIns3,5P 2 is carried out by PhosphoInositide Kinase
signalling pathway (Module 2: Figure PtdIns 3-kinase for five position containing a Fyve finger (PIKfyve),
signalling) that controls a number of cellular processes: which has a number of protein interaction domains
• It stimulates lipogenesis in white fat cells (Module 7: that enables it to interact with a number of other pro-
Figure lipolysis and lipogenesis). teins to form a functional PIKfyve--ArPIKfyve--Sac3

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