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BIOL301 Cell Signalling > Lecture 2 > Flashcards

Lecture 2 Flashcards

1
Q

What are the four main effects of insulin release?

A
  1. translocation of glucose transporters to the plasma membrane to stimulate glucose uptake
  2. activations glycogen synthase to stimulate glycogenolysis
  3. stimulates fatty acid production in liver and inhibit fat breakdown in adipose tissue
  4. suppresses gluconeogenesis in hepatocytes.
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2
Q

True or false: insulin is only produced as required by the body?

A

False

Insulin is produced in the beta cells of the islets of langerhans and stored in vesicles until needed for rapid response.

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3
Q

Describe the steps that lead to the production of proinsulin from pre-proinsulin

A

Insulin first made as pre-proinsulin, which has a signal peptide that directs it to the ER and where the signal peptide is cleaved to give proinsulin

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4
Q

Describe the steps that lead to the production of active insulin from proinsulin

A

Proinsulin has A, B and C chains. The C chain is removed by endocpeptidases

The remaining two arginine residues are removed by carboxypeptidases to give the active insulin molecule

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5
Q

What disulfide bonds exist within the insulin molecule? and what is their purpose?

A

2 disulphide binds between the A and B chains

A chain also has intramolecular disulfide bond

Purpose: hold the molecule together

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6
Q

What type of receptor is the insulin receptor?

A

Receptor Tyrosine kinase (RTK)

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7
Q

What is unique about the insulin receptor in comparison to other RTKs?

A

The insulin receptor is already dimerised (typically two RTKs will dimerise upon binding of a ligand to become active)

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8
Q

Describe the general structure of the insulin receptor RTK

A

Dimer - each monomer has an extracellular alpha chain with a cystine rich domain and a transmembrane/intracellular beta chain containing intracellular tyrosine kinase domain

There is disulfide bonding between the two receptor halfs

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9
Q

What is the proper name used to describe the insulin receptor?

A

α2-β2disulphide-bonded heterodimer

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10
Q

Describe the steps involved in the activation of the insulin receptor tyrosine kinases?

4 steps

A
  1. Insulin binds to extracellular alpha region
  2. conformational change in intracellular beta domain
  3. conformational change allows tyrosine kinases bind ATP and transfer the gamma phosphate to tyrosine on opposite activation lip (autophosphorylation of the activation lip) to activate the tyrosine kinases
  4. activated tyrosine kinases causes transautophosphorylation of many other tyrosine residues of intracellular domain
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11
Q

what is the activation lip of the tyrosine kinase?

A

it is a flexible loop that sterically hinders the substrate binding site (binding can only occur once phosphorylation of activation loop causes conformational change due to increase in negative charge)

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12
Q

Describe the steps involved in the recruitment of the insulin receptor substrate (IRS)

2 steps

A
  1. PTB domain of IRS binds to pY972 of insulin receptor
  2. binding brings IRS close to the tyrosine kinase domains resulting in phosphorylation at at least 9 different sites on IRS
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13
Q

Describe the structure of the insulin receptor substrate and the description of the role of each domain

A

PH domain, PTB domain and 9 conserved phosphorylation sites

PH domain binds phospholipids to localise the IRS close to the PM and insulin receptors

PTB domain binds to the pY972 of activated insulin receptor

Phosphorylation sites phosphorylated by tyrosine kinase of insulin receptor upon binding of PTB domain

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14
Q

What is the charge of a phosphate group bound to a substrate?

A

2-

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15
Q

What downstream pathways can the IRS activate?

A

PI3K (phosphatidyinositol-3-kinase) signalling pathway

MAPK signalling through binding of Grb2

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16
Q

How many members of the IRS family are there?

A

4 (IRS1-4)

17
Q

Which IRS members are important in insulin-stimulated glucose uptake?

A

IRS 1 sand IRS 2

18
Q

Describe the structure of the phosphatidyinositol-3 kinase (PI3K)

A

heterodimers with p85 and p110 subunits
p85 = twin SH2 domains and SH3 domain
p110 = lipid kinase domain

19
Q

How does PI3K phosphorylate phosphatidyinositol lipid substrate?

A

on the 3 position

20
Q

What does PI3K phosphorylate in response to activation by IRS?

A

PIP2 phosphorylated at position 3 to PIP3 second messenger

21
Q

How does PI3K bind to the insulin receptor substrate?

A

p85 SH2 domains bind to the pY of IRS2

22
Q

What is importance of binding PI3K close to the plasma membrane?

A

Its substrate PIP2 is membrane bound due to hyprophobic lipid tail so binding of PI3K to IRS brings it into close proximity with its PIP2 substrate

23
Q

How is PI3K activated?

A
  1. PI3K docks with IRS via SH2 domains binding IRS pY
  2. tyrosine kinase of insulin receptor phosphorylates p85 subunit
  3. activation of p110 lipid kinase allows dissociation of p110 from inhibitory p85 subunit
  4. p110 moves to lipid membrane to phosphorylate PIP2 to PIP3
24
Q

What is the difference between IP3 and PIP3?

A

IP3 has no phosphatidyl group (not lipid bound) so is feely diffusible second messenger

PIP3 has phosphatidyl group (lipid tail) and is membrane bound

25
Q

What is the purpose of second meseengers?

A

signal amplification

26
Q

How is Akt2/PKB fully activated?

A

PH domain of PKB/Akt2 sterically blocks active site
- PH domain binds to PIP3 and exposes the active site and activation lip of the PKB/Akt2
- PDK1 recruited to plasma membrane by binding of PH domain to PIP3
- PDK1 phosphorylates PKB/Akt2 at Thr308 of activation lip
- mTORC2 phosphorylates PKB/Akt at Ser473 for full activation

27
Q

What are the main roles of PIP3?

A

second messenger that is bound by certain PH domains (E.g. that of PKB/Akt2 and PDK1) required for full activation of PKB/Akt2

28
Q

How does PDK1 contribute to full activation of PKB/Akt2?

A

PDK1 phosphorylates PKB/Akt2 at Thr308 of activation lip

29
Q

How does mTORC2 contribute to the full activation of PKB/Akt2?

A

mTORC2 phosphorylates PKB/Akt2 at Ser473

30
Q

Give an overview of the steps involved in the activation of Akt2/PKB by insulin signalling

7 Steps

A
  1. insulin binds to receptor causing autophosphorylation and activation of tyrosine kinase domains
  2. IRS docks to insulin receptor via pY972 and PTB domain of IRS and is phosphorylated
  3. PI3K SH2 domains dock to phosphorylated IRS and is phosphorylated by tyrosine kinase of receptor to activate the lipid kinase domain
  4. PI3K converts PIP2 to PIP3
  5. PDK/Akt2 and PDK1 bind PIP3 via PH domains (active site of PDK/Akt2 revealed)
  6. PDK1 phosphorylates Thr activation lip of PDK/Akt2
  7. mTORC2 phosphorylates Ser to fully activate PDK/Akt2
31
Q

What are the 5 methods of regulation of the insulin pathway?

A
  1. SHIP2 removes 5-phosphate from PIP3 to remove the substrate completely (not direct reversal to PIP2)
  2. PTEN phosphatase directly reverses PIP3 to PIP2 by removing the 3-phosphate
  3. SHIP2 dephosphorylates the tyrosines on the insulin receptor and IRS
  4. Insulin receptor and associated complex endocytosed and recycled
  5. Glucagon opposes action of insulin

BIOL301 Cell Signalling (10 decks)

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