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5BBG0205 Molecular Basis of Gene Expression > L9: Insulin Signalling > Flashcards

L9: Insulin Signalling Flashcards

Learning outcomes: Gene expression must be regulated within an organism such that the appropriate genes are being expressed in relation to need The expression of many genes is regulated by hormones that allow co-ordinated regulation of gene expression Insulin regulates genes required for carbohydrate utilisation and protein synthesis This lecture will describe the types of genes that are regulated by insulin and the signaling pathway that controls their expression

1
Q

In multicellular organisms gene expression can be controlled by what?

A

signalling pathways

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2
Q

extracellular signals can prompt cells to do what?

A

Survive
Divide
Differentiate
Di

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3
Q

Ligands are known as what?

A

First messengers

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4
Q

How do ligands and receptors contribute to signaling pathways?

A
  • Ligands bind to cell surface receptors
  • this binding connects extracellular & intracellular environments
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5
Q

What are examples of ligands involved in signaling pathways?

A
  • Hormones
  • Cell surface proteins
  • Neurotransmitters
  • Short-range secreted factors (EGF, TNF, NGF, etc.)
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6
Q

What are examples of receptors involved in signaling pathways?

A
  • Receptor tyrosine kinases (RTKs)
  • G-protein coupled receptors (GPCRs)
  • Ionotropic receptors (ligand-gated ion channels)
  • Cytokine receptors
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7
Q

What happens when ligands bind to receptors in signaling pathways?

A

Ligand-bound receptors → conformational change → leads to activation of second messengers

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8
Q

What are examples of second messengers involved in signaling pathways?

A
  • Phosphatidylinositol-3-phosphate (PIP3)
  • Calcium ions (Ca2+)
  • Diacylglycerol (DAG)
  • Cyclic AMP (cAMP)
  • Arachidonic acid
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9
Q

What effects do second messengers have on gene expression and cellular processes?

A

→ production of second messengers triggers post-translational events.
→ leads to changes in gene expression/PTMs, (usually through phosphorylation).
→ second messengers can regulate target TFs or induce post-translational changes in proteins.

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10
Q

Where is insulin produced in the body?

A

→ Islets of Langerhans in the pancreas

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11
Q

What is the role of intravenous insulin in diabetes mellitus treatment?

A

→ an effective treatment for diabetes mellitus, (particularly type 1 diabetes)

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12
Q

significant about the discovery of insulin’s amino acid sequence?

A

→ first protein to have its AA sequence determined
→ consists of 51 AAs in its sequence

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13
Q

What type of receptor is the insulin receptor?

A

→ receptor tyrosine kinase (RTK)

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14
Q

What physiological processes does insulin regulate?

A

→ systemic and cell intrinsic processes

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15
Q

examples of physiological processes that insulin regulate?

A

→ Blood glucose homeostasis (Related disease: Diabetes)
→ Growth control (Related disease: Cancer)
→ Ageing (Related diseases: Age-related diseases)

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16
Q

What cellular processes are influenced by insulin?

A

→ Glucose uptake and glycogen/lipid metabolism
→ Cell size regulation
→ Cell proliferation and differentiation
→ Autophagy

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17
Q

How do diseases relate to insulin-regulated processes?

A
  • diabetes, cancer & age-related diseases associated with dysregulation of insulin-regulated processes.
    → e.g. diabetes linked to impaired blood glucose homeostasis regulated by insulin.
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18
Q

What is the dependence of various cellular processes on insulin?

A

all dependent on the ability of insulin to activate an intracellular signaling pathway

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19
Q

What are the key components and their roles in insulin receptor signaling?

A

→ Insulin acts as the ligand.
→ insulin receptor (IR) serves as receptor.
→ IRS (insulin receptor substrate) acts as the adaptor molecule.
→ PI3K (phosphoinositide 3-kinase) functions as the kinase.
PIP3 (phosphatidylinositol-3-phosphate) acts as second messenger.
→ PKB/AKT (protein kinase B) functions as the kinase.

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20
Q

What are the key steps in the insulin receptor signaling pathway?

A
  1. Insulin binds to the insulin receptor (IR).
  2. This binding leads to activation of IRS (insulin receptor substrate).
  3. IRS recruits and activates PI3K (phosphoinositide 3-kinase).
  4. PI3K phosphorylates phosphatidylinositol to produce PIP3 (phosphatidylinositol-3-phosphate).
  5. PIP3 acts as a second messenger, activating downstream signaling pathways.
  6. One key downstream effector: is PKB/AKT (protein kinase B), which is activated by PIP3.
  7. PKB/AKT phosphorylates target proteins → leading to various cellular responses e.g. glucose uptake, glycogen synthesis & cell survival.
21
Q

Where is PIP3 generated in the cell?

A

→ internal side of plasma membrane

22
Q

How does PIP3 facilitate the activation of AKT/PKB in the insulin signaling pathway?

A
  • PIP3 recruits AKT/PKB to membrane through its pleckstrin homology (PH) domain.
  • Once localized to membrane, AKT/PKB undergoes conformational changes that expose its kinase domain.
  • PDK1 (phosphoinositide-dependent protein kinase 1 & PDK2 are then recruited to membrane.
  • PDK1 phosphorylates AKT/PKB at threonine 308, activating it partially.
  • Full activation of AKT/PKB requires phosphorylation at serine 473 by PDK2.
23
Q

What is the structure of PKB/AKT?

A

PKB/AKT structure includes:
PH domain (yellow)
CAT: Catalytic domain
EXT: C-terminal extension
Peptide substrate (green)
HM: Hydrophobic motif
(colours correspond to slide 13)

24
Q

What are the phosphorylation sites of PKB/AKT?

A

Thr308: Located between kinase subdomains 7 and 8 in the ‘activation T loop’
Ser473: Located in the hydrophobic motif (HM)

25
Q

How is PKB/AKT phosphorylated and activated?

A
  • Upon cell stimulation, PKB is phosphorylated on both Thr308 and Ser473.
  • Phosphorylation of Thr308 is mediated by PDK1, which is recruited to the membrane by PIP3.
  • Phosphorylation of Ser473 is mediated by another kinase, possibly PDK2.
  • Mutation of Thr308 and Ser473 to Ala abolishes PKB activity.
26
Q

What are the common components shared by all insulin signaling cascades?

A

Insulin
Insulin Receptor
IRS (Insulin Receptor Substrate)
PI3K (Phosphoinositide 3-Kinase)
PIP3 (Phosphatidylinositol-3-Phosphate)
PTEN (Phosphatase and Tensin Homolog)
PKB/AKT (Protein Kinase B / AKT)
Downstream Targets

27
Q

Describe the key components and interactions in the insulin/IGF signaling pathway

A

Insulin/IGF: Ligand for IR
IR: RTK undergoes transphosphorylation and recruits IRS
IRS: Contains phospho-tyrosines which associate with the SH2 domain in p85 of PI3K
PI3K: Heterodimer of regulatory (p85) and catalytic domain (p110) that catalyzes the conversion of PIP2 to PIP3
PIP3: Phosphatidylinositol (3,4,5) triphosphate
PTEN: Phosphatase that converts PIP3 to PIP2
PKB/AKT: Protein kinase B, Ser/Thr PH domain kinase. PH domain associates with PIP3. Once at the membrane, PKB is activated by PDK1/PDK2

28
Q

What systemic and cell intrinsic processes can insulin regulate?

A

Blood glucose homeostasis
Growth control
Ageing

29
Q

What are the tissue-specific responses to insulin in glucose homeostasis?

A

Skeletal muscle and adipose tissue respond to insulin by:

Increasing glucose uptake (via Glut4)
Increasing glycogen synthesis (in muscle)
Increasing lipid synthesis (in adipose tissue)

30
Q

how does insulin regulate glucose production in the liver?

A

(in liver) insulin inhibits glucose production and release by:
→ Blocking gluconeogenesis (glucose synthesis from non-carbohydrate precursors)
→ Blocking glycogenolysis (breakdown of glycogen into glucose)
- Glut2 transports glucose bidirectionally in the liver, kidney, and pancreas.

31
Q

What is the role of insulin in glucose homeostasis?

A

Insulin is secreted by pancreatic β cells, which express Glut2.
Insulin signaling regulates glucose homeostasis in various tissues

32
Q

How is glucose transported in tissues such as the liver, kidney, and pancreas?

A

Glut2 transports glucose bidirectionally in tissues such as the liver, kidney, and pancreas.

33
Q

What mediates the glucose-dependent release of insulin into the bloodstream?

A
  • a rise in Ca2+ concentration in pancreatic β cells.
34
Q

How is glucose uptake regulated in the brain and other organs?

A
  • it is constitutive and not regulated by insulin, facilitated by Glut1 transporters.
35
Q

How does insulin signaling regulate glucose homeostasis in muscle?

A

involves both transcriptional and post-translational mechanisms.

36
Q

What is the role of insulin in transcriptional regulation in muscle?

A
  • regulates expression of key enzymes involved in glucose metabolism
    -such as PEPCK (phosphoenolpyruvate carboxykinase) → which catalyzes rate-limiting step in gluconeogenesis.
37
Q

How does insulin promote glucose uptake in muscle cells?

A
  • Insulin promotes translocation of Glut4 transporters to the plasma membrane, increasing glucose uptake into muscle cells.
38
Q

What is the role of AS160 in insulin signaling in muscle?

A
  • AS160 (Akt Substrate of 160 kDa) = downstream target of AKT.
  • AS160 controls Rab proteins → which regulate microtubule cytoskeleton to facilitate movement of Glut4-containing vesicles to the cell membrane, enhancing glucose uptake
39
Q

Describe the mechanism of insulin signaling in muscle.

A
  • Insulin binds to its receptor on surface of muscle cells.
    → binding activates the insulin receptor, leading to autophosphorylation & recruitment of IRS proteins.
    → IRS proteins then activate downstream signaling pathways, including the PI3K pathway.
    Activation of PI3K → production of the second messenger PIP3
    → PIP3 recruits AKT/PKB to plasma membrane, where it becomes activated.
    → Activated AKT/PKB phosphorylates various substrates, including AS160
    → Phosphorylation of AS160 facilitates the translocation of Glut4 transporters to the cell membrane → ↑ glucose uptake into muscle cells.
40
Q

How does insulin signaling regulate glucose homeostasis in the liver?

A

involves both transcriptional and post-translational mechanisms.

41
Q

What are the transcriptional mechanisms of insulin signaling in the liver?

A

→ insulin stimulates the expression of genes encoding glycolytic & fatty acid synthetic enzymes
→ Insulin inhibits expression of gluconeogenic enzymes

42
Q

What are the post-translational mechanisms of insulin signaling in the liver?

A

Insulin regulates the activity of key enzymes involved in glucose metabolism.
→ Activation of Phosphofructokinase-1 (PFK-1) promotes glycolysis.
→ Activation of Pyruvate Kinase (PK) enhances the conversion of phosphoenolpyruvate to pyruvate.
→ Inhibition of Phosphoenolpyruvate Carboxykinase (PEPCK) suppresses gluconeogenesis.
→ Activation of Acetyl-CoA Carboxylase (ACC) promotes fatty acid synthesis.
→ Insulin also regulates the activity of glycogen synthase (GS) and glycogen phosphorylase (GP) through changes in phosphorylation state.

43
Q

How does insulin signaling influence organ size?

A

controls organ size by regulating both cell size and cell proliferation

44
Q

What is ‘Leprechaunism’ in humans?

A
  • rare genetic disorder characterized by severe insulin resistance → resulting in impaired growth & development.
45
Q

How does insulin signaling control growth?

A
  • through both transcriptional and post-translational mechanisms.
46
Q

What are the targets of PKB/AKT in insulin signaling?

A
  • PKB/AKT phosphorylates several different targets that contain a XXXXX motif.
  • Many of these proteins are key regulators of cell growth and survival.
  • Due to its role in regulating cell growth & survival, PKB/AKT is a major drug target in cancer treatment.
47
Q

How does insulin signaling influence aging?

A

Insulin signaling affects aging through a mechanism involving FoxO.

48
Q

What is the role of FoxO in aging?

A
  • FoxO, when overexpressed in the fat body, plays a role in controlling aging.
  • FoxO interacts with SIRT1, contributing to its role in the regulation of aging

5BBG0205 Molecular Basis of Gene Expression (9 decks)

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