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Medsci 312 > Lecture Six; Cell signalling Three > Flashcards

Lecture Six; Cell signalling Three Flashcards

1
Q

What are cytokines?

A

Small molecules that act like hormones

i.e
IL
Interferons
TNF
Growth factors
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2
Q

What seperates cytokines from other hormones?

A

They can be secreted by multiple organs

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3
Q

What are cytokines traditionally seen as?

A

The drivers of heamopoetic systems, but they have many more roles than this

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4
Q

Describe type one cytokine receptors;

most common

A
  • Many different types of receptors, usually heterodimers or trimers
  • Dont have intrinsic catalytic activity
  • Have tightly associated tyrosine kinase molecules called Janus Kinase (JAK)
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5
Q

What do JAK / cytokine receptors signal through?

A
  • STATS (signal trasducer and Activator of transcription)
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6
Q

Describe the step 1 following IL6 binding to cytokine type 1 JAK-STAT signalling pathway;

1/6

A
  • IL6 binds
  • 3D conformational change of transmembrane receptor
  • This causes signalling to the JAK
  • JAK phosphorylates domain on the receptor, the AA sequence is perfect now for SH2 domain on STAT to bind.
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7
Q

Describe the step 2 following IL6 binding to cytokine type 1 JAK-STAT signalling pathway;

2/6

A

STATS are now recruited to the receptors via their SH2 domains where the STATs themselves become tyrosine phosphorylated by the JAK molecules

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8
Q

Describe the step 3 following IL6 binding to cytokine type 1 JAK-STAT signalling pathway;

3/6

A

Tyrosine phosphorylated STATs are able to form dimers with the SH2 domain of each binding to the others p-Tyr

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9
Q

Describe the step 4 following IL6 binding to cytokine type 1 JAK-STAT signalling pathway;

4/6

A

Dimerised STATs can move to the nucleus and induce expression of certain genes that have STAT binding sites in their promoter

Gene expression!!!!!

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10
Q

Why are there 2 stats dimerising the DNA?

A

2 STATS for tight clamping effect on the DNA

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11
Q

Describe the step 5 following IL6 binding to cytokine type 1 JAK-STAT signalling pathway;

5/6

A

Following gene upregulation

STATs also stimulate the production of is Supressor of Cytokine Signaling (SOCS) molecules

These are part of a negative feedbacks system

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12
Q

Describe the step 6 following IL6 binding to cytokine type 1 JAK-STAT signalling pathway;

6/6

A

SOCS molecules have an SH2 domain which can compete with STATs for binding to receptors and so inhibit signaling

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13
Q

Do type 1 cytokine signalling molecules always use STATS?

A

STATs are recruited to all type-1 and Type2 cytokine receptors but other SH2 domain containing proteins can also be recruited - the exact types of SH2 domain containing proteins varies between receptors

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14
Q

What sort of mechansim is the type 1 cytokine receptors?

A

This system is a mechanism for letting a cell surface receptor induce gene expression

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15
Q

write some notes on type 2 cytokine receptors;

A
  • Interferon receptors
  • Function similarly to type one
  • Requires stat 1 and 2

Subtle variations in STATs = range of functionality

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16
Q

What do signalling pathways depend on?

A
  • Depends on which receptors, signalling molecules are expressed as to what can happen
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17
Q

What else signals via the JAK/STAT pathway? and what are the implications of this?

A

Prolactin
Growth hormones

  • Networks inside cells are complicated and cell specific
  • Prolactin and growth hormones signal via similar pathways but have completely different outcomes

Cell dependancy for signalling outcomes

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18
Q

What does the TGF family of cytokines include?

A

TGFb, activins and Bone morphogenic peptides (BMPs)

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19
Q

What is the function of TGF cyotkines?

A

These are involved in regulating growth, differentiation and cell migration, especially during development

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20
Q

What receptors do TGF cytokines act on?

A

All function via Receptor Ser/Thr Kinase

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21
Q

Describe the Ser/Thr kinase receptor;

A
  • Two receptors;
  • TGFb receptor type One and Two
  • Both have intracellular Ser/Thr kinase domains
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22
Q

What is step 1 in the TGF signalling?

A

TGFb binds, type 1 and 2 receptors dimerise

-transphosphorylation of Ser/Thr domains occurs

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23
Q

What is step 2 in the TGF signalling?

A

Smad 2 and 3 are Receptor regulated SMADS (R-SMAD) and are phosphorylated by Type-I Receptor (after it is transphosphorylated)

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24
Q

What is step 3 in the TGF signalling?

A

Phosphorylation of Smad 2 and 3 allows them to associate with the common mediator SMAD4 (Co-SMAD)

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25
Q

What is step 4 in the TGF signalling?

A

This complex can now move to the nucleus and act as a transcription factor

Gene expression!!!

26
Q

How is the TGF signalling regulated?

A

Smad 6 and 7 are inhibitory SMADS (I-SMADs) and can block signalling via R-Smads

Feedback inhibition

27
Q

What produces TNF?

A

Monocytes

Therefore tends to be elevated in sites of inflammation

28
Q

What does TNF play a role in?

A

Plays a key role in promoting inflammation

Evidence it is involved in inducing insulin resistance that arises from excess fat deposition and modulation of the immune system in cancer.

Elevated TNF alpha levels have been implicated in the pathogenesis of inflammatory diseases i.e rheumatoid arthritis

Number of drugs target this to reduce inflammation

29
Q

Describe the TNF receptor;

A
  • Trimer
  • IC death dominas that is bound to Son of Death Domain (SODD) when TNF is not bound

No enzymatic activity

30
Q

Describe step one in TNF signalling;

1/3

A

TNF binding to the outside of the cell causes a shape change in the receptor inside of the cells which means SODD can no longer bind

achieved solely by protein conformational change

31
Q

Describe step 2 in TNF signalling;

2/3

A

Now binding of TRADD is favored instead

32
Q

Describe step 3 in TNF signalling;

3/3

A

TRADD in turn can bind to other proteins (note that this does not require any phosphorylation in this case, just the shape change)

This forms specific complexes of proteins that can do specific things

i.e apoptosis

33
Q

What other pathway is activated in TNF signalling?

A

One other very important pathway activated is called the NFKappaB pathway

34
Q

Prior to the NFKappaB pathway activation what is happening

A

In unstimulated cells Inhibitor of Kappa Kinase (IKappaB) binds to Nuclear Factor Kappa B (NFKB) sequestering the whole complex in the cytosol

35
Q

What is the first step in the NFKappaB pathway activation ?

A

After TNF stimulation ;
Inhibitor of Kappa Kinase Kinase (IKK) gets phosphorylated by RIP which activates IKK

(this is bound to TRADD)

36
Q

What is the step 2 in the NFKappaB pathway activation ?

A

This can now phosphorylate Inhibitor of Kappa Kinase which is degraded

(ubiquination)

(cell signalling pathways can control protein regulation by protein degradation)

37
Q

What is the step 3 in the NFKappaB pathway activation ?

A

NFKB is now transported to nucleus where it acts to upregulate genes involved in inflammation

38
Q

What is a common method of anti-inflams?

A

3 of 5 top selling drugs in world block TNF- a Signalling by mopping up TNF-a

i.e
Monoclonal antibodies
- Humira
- Remicade
- Enbrel
39
Q

What are Wnts?

A

Wnts are a family of about 19 autocrine hormones

40
Q

What do Wnts do?

A

Wnt signalling very important in embryo development and maintenance of stem cells

Also important certain types of cancer e.g the polyps that precede full blown bowel cancer are driven by mutations in APC and many liver cancers have mutations in beta-catenin which make it permanently stable

41
Q

How do Wnts commonly signal?

A
  • Most of these signal by regulating the level of a protein called beta-catenin
  • The excess beta-catenin in the cytosol is normally phosphorylated and degraded by the proteasome
  • Wnts block this phosphorylation and so cause an increase in beta-catenin in the cytosol which then moves to the nucleus to activate a very specific subset of genes
42
Q

Where is Beta catenin found in the asbence of signal?

A

(in excess)

In the cytosol, where it is part of a IC destruction complex. It is frequently being degraded

43
Q

Describe step one of beta catenin degradation in the absence of signal;

A

CK1 primes this degradation by phosphorylating B-catenin

44
Q

Describe step two of beta catenin degradation in the absence of signal;

A

CSK phosphorylates Beta catenin

45
Q

Describe step three of beta catenin degradation in the absence of signal;

A

In the absence of signal the phosphorylated beta catenin separates from the destruction complex and undergoes proteosomal degradation

46
Q

What is the function of the destruction molecule?

A

Gives a way for the cells to be able to respond very quickly (degradation keeps occurring to ensure there isnt too much of it)

  • Have mechanisms that can stablise it
47
Q

Describe the Wnt receptor;

A

LRP 5 or 6 bound to 12 frizzled proteins

48
Q

Describe step one of Wnt signalling;

A

Wnt (autocrine)

Wnt Signaling Induces Conformational Change in Beta Catenin Signaling Complex

So GSK3 Phosphorylates LRP instead of Beta-catenin

Beta-catenin now can’t be phosphorylated so it doesn’t degrade so it starts to accumulate

49
Q

Describe step two of Wnt signalling;

A

As the beta catenin levels rise it is transported to nucleus where it acts as a transcription factor to upregulate genes involved in cell growth such as Cyclins and Myc

50
Q

What are some additonal functions of beta catenin?

A
  • Can bind cell surface molecules i.e adherins junctions

B-catenin binds A catenin which binds filaments regulating cell shape

51
Q

Other than hormone driven mechanisms what else can cells respond to?

A

Their environment i.e

  • Glucose mediated secretion of insulin (covered later in the course)
  • Activation of AMP-kinase by low nutrient status
  • Activation of SREBP transcription factor by low cholesterol
  • Free radicals
  • Sensing levels of amino acids
52
Q

Describe AMP as a signalling molecule;

A

When levels of ATP are low ADP can be used to regenerate some ATP but this also generates AMP and this acts as a signal to the cell to say that energy levels are low by activating AMP-K

(gauge of cell energy)

AMP is bad as can form uric acid

53
Q

Describe how AMP activated protein kinase acts a signalling mechanism;

step one

A

AMP binding to gamma subunit changes its conformation so it is now a substrate for phosphorylation by LKB1

54
Q

Describe how AMP activated protein kinase acts a signalling mechanism;

step two

A

This in turn changes conformation of the catalytic subunit which can then induce phosphorylation of downstream targets which will stimulate uptake and use of alternative nutrients and shut down unnecessary cell functions

55
Q

What are some examples of downstream effects of AMP - activated protein kinase signalling;

A
  • Stimulates glucose uptake in muscle
  • Stimulates fatty acid oxidation as an energy source
  • Reduces protein translation to conserve cellular energy
56
Q

How can cholesterol act as a signalling molecule;

A

In the presence of high cholesterol levels in cell membranes SREBP exists as an integral membrane protein bound to SCAP

57
Q

What happens to SERBP in low cholesterol levels?

A

In the presence of low cholesterol levels in cell membranes SREBP is cleaved releasing part of the molecule (bHLH) that is now a functional transcription factor. It upregulates genes involved in increasing cholesterol levels

58
Q

Describe the sources of ROS in the cytosol;

A

NADPH oxidase on the plasma membrane

Leakage of electrons from the ETC in the mitochondria

59
Q

How can free radicals regulate siganlling?

A

ROS regulate

Phosphotyrosine Phosphate (PTP)

and

PTEN

H2O2 interactions deactivate these proteins indicating excess ROS

60
Q

What does the translation of mRNA always start from?

A

ATG coding for MET

This requires eIF2alpha (transcriptional factor)

61
Q

What happens when AA levels are low in terms of transcription?

A

When amino acids low then many tRNA molecules uncharged and this activates GCN2 which phosphorylates and inactivates eIF2alpha

= So translation cant start

Medsci 312 (28 decks)

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