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biol301 cell signalling > Lecture 4: FoxO and Insulin-like receptors > Flashcards

Lecture 4: FoxO and Insulin-like receptors Flashcards

1
Q

What is the name of the family of transcription factors involved in insulin signalling pathway?

A

FOXO

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2
Q

Which FOXO family member is expressed at high levels in insulin-responsive tissues?

A

FOXO1

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3
Q

Describe the structure of FOXO transcription factor DNA binding domain

A

DNA binding domain consists of three alpha helices, three beta strands, and two wings
- the alpha helices recognise a particular DNA sequence and allow binding of FOXO within the major groove of the DNA strand
- the wings recognise the phosphate backbone

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4
Q

How are FOXO transcription factors regulated?

A
  • phosphorylation by Akt/PKB, CK1 (casein kinase 1) an DYRK1
  • acetylation (addition of carboxy group to lysine side chains) by CBP and PCAF
  • deacetylation by sirtuins
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5
Q

Describe the main domains of FOXO transcription factors

A

L1 and L2 = nuclear localisation sequences
E1, E2, and E3 = nuclear export sequences
DNA binding domain
Transactivation domain

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6
Q

How does FOXO phosphorylation result in transcriptional inactivation by insulin signalling?

A

Insulin signalling activates Akt/PKB, which phosphorylates FOXO
- 14-3-3 dimer recognises and binds to the phosphorylation sites and sterically blocks the nuclear localisation sequences (L1 and L2) and DNA binding domain
- Ran and Crm-1 bind to phosphorylated FoxO resulting in nuclear exclusion

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7
Q

Describe the structure of 14-3-3 proteins

A

Dimer
each monomer has 9 alpha helices and binds to phosphoserine/phosphotheronine motifs in a sequence specific manner

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8
Q

Describe the movement of FOXO from the cytosol to the nucleus under basal conditions

A

Importin will bind to NLS along with Ran (GDP form) to promote translocation into the nucleus, DNA binding and gene transcription

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9
Q

Describe the movement of FOXO from the nucleus to the cytosol under basal conditions

A

Crm1 bind to Ran (GTP form) at nuclear export sequences resulting in FOXO export from the nucleus

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10
Q

Under basal conditions, where is the majority of FOXO located?

A

Nucleus

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11
Q

Explain how insulin signalling affects nuclear import and export of FOXO

A
  • Akt/PKB phosphorylates FOXO, 14-3-3 binds by recognising phosphoserine/theronine residues, blocks NLS, prevents importin binding and no nuclear import of FOXO
  • Akt/PKB phosphorylates FOXO, Ran and Crm1 bind to nuclear export sequences and promotes export to the cytosol
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12
Q

In response to insulin signalling, where is the majority of FOXO located?

A

cytoplasm

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13
Q

What are some of the roles of FOXO transcription factors?

A

Inhibit cellular proliferation
promote apoptosis
enhance resistance to oxidative stress
regulate metabolism through their effects in the liver, muscle, adipose tissue and pancreas
increase longevity
(overall action of promoting quiescence, inhibiting growth and cellular proliferation)

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14
Q

How can FOXO gene activation oppose the action of insulin?

A

in hepatocytes and pancreatic beta cells, FOXO gene activation results in increased blood glucose through decreased insulin secretion

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15
Q

Other than through regulation of FOXO, how else can insulin signalling regulate gene expression?

A

Activation of the MAPK pathway to stimulate survival, proliferation and differentiation

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16
Q

How does insulin signalling via FOXO and MAPK pathway promote proliferation?

A

Insulin signalling inhibits FOXO gene activation to prevent apoptosis and promote survival

Insulin signalling via the MAPK pathway to promote expression of genes that improve proliferation and development

17
Q

Explain how insulin signalling activates the MAPK pathway

A
  • Insulin binds to insulin receptor
  • conformational change, transautophosphorylation of the tyrosine kinase domains
  • SHC binds to phsophotyrosines on insulin receptor
  • SHC phosphorylated by receptor tyrosine kinase
  • Grb2 SH2 domains recognise and bind to phosphorylated SHC
  • Twin SH3 domains of Grb2 recognise proline rich motifs in SOS protein
  • SOS is a guanidine exchange factor for Ras
    (small membrane bound GTPase) - SOS promotes exchange of GDP to GTP
  • activated Ras-GTP activated MAPK phosphorylation pathway (MAPKKK activated by Ras, activates a MAPKK, which then activates the MAPK (E.g. ERK))
  • phosphorylated MAPK (E.g. ERK-P) translocates to nucleus and phosphorylates transcription factors that stimulate survival, proliferation and differentiation.
18
Q

What are similarities and differences between Insulin and Insulin-like growth factors (IGFs)?

A

unlike insulin, whose C-peptide chain is cleaved form pro-insulin to give the active insulin, the A, B and C peptide chains of IGFs remain attached.

IGFs and insulin are highly homologous (as are their receptors)

19
Q

How many IGFs are there?

A

2
(IGF-I and IGF-II)

20
Q

Where are IGFs mainly produced?

A

Liver (stimulated by action of growth hormones)

21
Q

Where do IGFs mainly act?

A

directly stimulate bone and cartilage growth

22
Q

True or false: IGFs have a major role in growth regulation prenatally (before birth)

A

True

23
Q

What is unique about the expression of IGFs?

A

There are only expressed on the paternal allele (genetic imprinting - maternal allele silenced - maternally imprinted allele indicates its key role as a regulating factor in foetal growth and development)

24
Q

What results from forced expression of IGF-I in mouse muscle?

A

Hypertrophy (size of cells increase rather then number) - much larger mice

25
Q

How is interaction with IGF and Ins with their receptors similar?

A

Due to structural homology between the ligands and their receptors, there is similar interaction of ligands with the L1 and CR regions of the receptors

26
Q

What can result from structural similarities between IGFs/Ins and the receptors?

A

Overlapping specificity

27
Q

How does specificity overlap between the insulin receptors and insulin-like growth factor receptors?

A

IR-A isoform binds insulin, IGF-2 (with lower affinity), and IGF-1 (with lower affinity)
IR-B isoform binds insulin and IGF-1 (with lower affinity)
IGF-1R binds IGF-1, IGF-2, and insulin (with lower affinity)

28
Q

What is the structure of the IGF-R1?

A

alpha2beta2 homodimer (but can also form heterodimers with Insulin receptor)

29
Q

How does the heterodimeric nature of the INS and IGF receptors affect specificity of receptors?

A

hybrid receptors can form in which half of the alphabeta from the insulin receptor and half from the IGF receptor
- these hybrid receptors have been detected in all cells co-expressing IR and IGF-1R
- these hybrid receptors behave like IGF-1R in that they bind IGF-1, IGF-2, and insulin (with lower affinity)

30
Q

How does signalling from the IGF-1 receptor work?

A

Basically identically to insulin receptor signalling:
- activation of Akt/PKB via IRS1/2 and PIP3 to have metabolic effects via inhibition of FOXO and GSK-3beta
- activation of MAPK pathway via Grb2/SOS to phosphorylate ERK MAPK that promotes growth

31
Q

How is gene expression regulated via Akt during Insulin and IGF signalling?

A
  • PI3K and Akt/PKB active
  • Akt phosphorylates FOXO
  • 14-3-3 protein binds FOXO (blocks nuclear localisation sequence and DNA binding domain - prevents importin binding)
  • genes for quiescence or apoptosis normally activated by FOXO are not expressed
    (this results in cell survival and growth in a high glucose environment)
32
Q

How is gene expression regulated via MAPK during Insulin and IGF signalling?

A
  • Ras-GDP and MAPK cascade activated
  • phosphorylated ERK1 translocates to the nucleus
  • transcription factors are phosphorylated and activated
  • genes for proliferation, differentiation and development expressed
    (this results in cell survival and growth in a high glucose environment)
33
Q

Give two similarities between the Akt/PKB and MAPK pathways?

A
  1. promote survival and proliferation
  2. regulate gene expression through phosphorylation of trans-acting factors (indirect action by phosphorylating factors that translocate to the nucleus to control transcription) involved in transcriptional control
34
Q

Give three differences between the Akt/PKB and MAPK pathways

A
  1. Distinct mechanisms of activation (Akt/PKB via IRS1/2, PI3K, PIP3) (MAPK via Grb2, SOS)
  2. Opposite effects of gene regulation (Akt/PKB suppresses apoptosis and quiescence, whereas MAPK promotes proliferation)
  3. Akt/PKB pathway has many additional metabolic and pro-survival effects.

biol301 cell signalling (10 decks)

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