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B301 > L2, Akt Activation > Flashcards

L2, Akt Activation Flashcards

1
Q

Briefly list the 4 functions of insulin in metabolism

A
  1. Stimulate uptake of glucose by the cell
  2. Stimulate glycogenesis
  3. Stimulate fatty acid production in liver, inhibit fat breakdown in adipose tissue
  4. Suppress gluconeogenesis
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2
Q

How is insulin produced?… Outline

A
  • Produced by beta islets of langerhans
  • Stored in vesicles until required -> Facilitates rapid response
  • Secreted by pancreas when required -> Facilitated by rich blood supply
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3
Q

How is insulin produced?…Moleular Specifics

A
  • Transcribed as pre-proinsulin (pre = signal peptide)
  • Signal peptide directs molecule to ER for processing
  • Proinsulin has C chain removed by endoproteases
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4
Q

Proinsulin structure

A
  • Consists of A, B and C chain
  • Extensive disulfide bonding within molecule ensures structure holds when parts are cleaved
  • Only B and A remain in insulin form
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5
Q

Features of the insulin receptor

A
  • Type of receptor tyrosine kinase
  • Usually predimerised
  • Not freely diffusible
  • Propagates signal to the nucleus
  • A and B isoforms
  • Found on insulin responsive muscle, hepatic and adipose tissue
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6
Q

Structure of insulin receptor

A
  • Alpha chain outside cell (cysteine rich -> disulfide bonded) beta-sheets across membrane (flexible, TK activity within cell)
  • Binding domain transmits information across membrane to kinase domain
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7
Q

How does insulin binding to IR activate the PI3K and MAPK pathways?

A
  1. Insulin binds to alpha region of receptor
  2. Conformational change in I-C beta domain triggered
  3. Tyrosine kinase activated, binds ATP
  4. Transautophosphorylation of receptor on tyrosine (usually Y972) -> tyrosine activation lip
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8
Q

What are the broad effects of the PI3K and MAPK pathways?

A

PI3-Kinase: Metabolic effects via GLUT4 translocation and FOXO transcription factors
MAPK: Cell growth, proliferation

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9
Q

How do most RTKs differ from the IR?

A
  • Most RTKs dimerise upon ligand binding
  • Insulin receptor, however, is typically predimerised
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10
Q

Structure of Insulin Receptor Substrate

A

IRS
* 4 members of family (IRS1-4)
* PH domain (helps localise substrate close to membrane)
* PTB domain (binding domain)
* 9 conserved phosphorylation sites

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11
Q

IRS role in insulin signalling

A

…pY972 after ligand binding to IR
1. IRS PTB domain binds pY972 of IR
2. IRS multiply pY phosphorylated by insulin RTK
3. Activates PI3-K signalling pathway / binds Grb-2 -> MAPK

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12
Q

What evidence illustrates the important role of IRS1 and 2?

A
  • Deleting either isoform leads to insulin resistance
  • As such, they are both important in insulin-stimulated glucose uptake
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13
Q

Phosphatidylinositol-3 kinase (PI3K) structure and binding:

A
  • Heterodimeric protein, p85 and p110 subunits
  • p85 domains: SH3, SH2, p110 interaction, SH2
  • p110 domains: p85 interaction. ras interaction, lipid kinase
  • SH2 domains on p85 bind t pY on IRS2, bringing PI3K close to its substrate, PIP2
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14
Q

How does PI3K interact with PIP2?

A
  • Phosphorylates on the 3 position -> PIP2 to PIP3
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15
Q

Is PIP2 freely diffusible?

A

No, the majority of the phosphate head group is embedded in the membrane with target at the surface

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16
Q

Describe in detail how PI3K is activated and its activity:

A
  1. PI3K docks with IRS​
  2. Insulin RTK phosphorylates PI3K p85 subunit​
  3. This leads to activation of p110 lipid kinase ​
  4. p110 dissociates and moves to the lipid membrane​
  5. p110 lipid kinase phosphorylates PIP2 to form PIP3​
17
Q

What opposes PI3K?

A
  • PTEN is a lipid phosphatase which regenerates PIP2 from PIP3
  • As such, PI3K signalling is reversible
18
Q

What is the role of PIP3?

A

Acts as a second messenger…
* Binds PH domain on Protein Kinase B (Aka. Akt), revealing the activation lip -> partially activated PKB
* PDK1 binds PIP3 via PH domain, activating kinase activity -> phosphorylates PKB * mTORC2 also phosphorylates PKB -> Fully active PKB/Akt

19
Q

Akt/PKB structure:

A
  • Serine/threonine kinase
  • Three isoforms
  • PH domain inhibits activity unless bound to PIP3
  • Thr308: Phosph. by PDK1
  • Ser473: Phosph. by mTORC2
20
Q

How is the insulin pathway regulated?

A
  • SHIP2: removes 5-phosphate from PIP3 -> PI-3,4-P2, also dephosphorylates pY on insulin receptor and IRS
  • PTEN removes 3-phosphate -> PI-4,5-P2
  • Insulin receptor endocytosis and recycling
  • Glucagon opposes insulin action
21
Q

+ Why is PKB inactive in the cytosol?

A
  • PH domain blocks kinase active site
  • Upon ligand binding, PH binds PI3K, so the kinase activity can proceed (partially then fully activated by PDK1, mTORC2)

B301 (15 decks)

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