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CHEMISTRY 4360 MIDTERM > Signalling by Cytokines > Flashcards

Signalling by Cytokines Flashcards

1
Q

What do cytokines do and help with?

A
  1. Proliferation, differentiation, and function of the immune system.
  2. Differentiation of cells in the blood forming system.
  3. Inflammation, including acute phase response.
  4. Antiviral responses.
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2
Q

What five components do the cytokines include?

A
  1. Interleukins.
  2. Interferons.
  3. Erythropoietin and Thrombopoietin
  4. Growth Hormone and Prolactin.
  5. Leptin.
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3
Q

What are interleukins?

A

A cytokine, that signals between leukocytes, especially in the immune response and uses the cytokine pathway.

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4
Q

What are interferons?

A

First discovered for antiviral properties.

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5
Q

What does erythropoietin and thrombopoietin do?

A

Promote development of RBC (EPO) and platelets (TPO).

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6
Q

What is leptin?

A

The obesity hormone.

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7
Q

What are the two components of cytokine type receptors?

A

The membrane bound component and the associated tyrosine protein kinase.

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8
Q

What is the membrane bound component of cytokine receptors?

A

Has extracellular, cytoplasmic domains and a single transmembrane. May consist of multiple polypeptides depending on the ligand.

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9
Q

What is the associated tyrosine protein kinase (TPK)?

A

This is a SEPARATE polypeptide, but bound tightly to the cytoplasmic domain of the receptor.

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10
Q

What are the four cytokine-linked TPKs?

A
  1. JAK1
  2. JAK2
  3. JAK3
  4. TPK2
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11
Q

What are the three chains that make up the cytokine?

A

a, B, gamma.

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12
Q

What does the alpha chain do?

A

The alpha chain forms most of the ligand-binding site, and is unique to that receptor.

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13
Q

What do the beta and gamma chains do?

A

They are found in more than one cytokine receptor, and are called common chains.

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14
Q

Where do all three chains exist?

A

All three chains span the membrane with a single TM domain.

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15
Q

What type of receptors are the cytokine receptors?

A

Type 1, meaning there is WSXWS motif in the extracellular domain where Type 2 lacks this.

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16
Q

What do the cytoplasmic domain chains hold?

A

A box 1 motif, including a consensus sequence of that box that is needed for interaction with the JAK receptor. Different receptor chains will bind different JAKs.

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17
Q

How does the mechanism of the cytokine receptors work?

A

Exactly like the growth factor receptors.

  1. Cytokine receptor dimerizes when ligand is bound to it.
  2. This brings two JAKs together on the cytoplasmic side.
  3. The JAKs phosphorylate each other on key Tyr residues.
  4. In turn, autophosphorylation becomes activated.
  5. The pTyr residues created on JAK now act as binding sites for the SH2 domains.
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18
Q

What is one key difference between the cytokine receptors and growth factor receptors?

A

The TPK activity in cytokine receptor signalling is in a SEPARATE but associated polypeptide.

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19
Q

Now that the pTyr residues on JAK as created binding sites, what binds do this site?

A

Cytoplasmic proteins called STAT proteins that can bind using SH2 domains.

20
Q

What does STAT stand for?

A

Signal transduction and activator transcription.

21
Q

What is STAT made up of?

A

A DNA binding domain, an SH2 domain, and a conserved Tyr residue near the C terminus.

22
Q

How do STAT proteins ultimately get into the nucleus and activate transcription of target genes? (6 Steps.)

A
  1. Once the SH2 of a STAT protein binds to the pTyr of the JAK, the JAK phosphorylates the STAT on the conserved Tyr near the C-terminus.
  2. Now each STAT has both a pTyr and an SH2 domain.
  3. IF these two items are present, two STAT monomers can dimerize.
  4. These dimers are seen and can then move into the nucleus.
  5. In some cases, extra protein factors must also bind first.
  6. In the nucleus, the STAT dimer is recognized and can bind to specific DNA sequences in order to activate transcription of certain target genes.
23
Q

Define a homodimer?

A

Two STAT1 monomers: 2 of the same proteins.

24
Q

Define a heterodimer?

A

A STAT1 and STAT2 dimerization: 2 different proteins.

25
Q

Give an example pathway of a STAT protein working its way into the nucleus and transcribing genes?

A
  1. IFN (interferon) a and B bind to the IFN receptor of target cells.
  2. This activates JAK1 and TYK2.
  3. These protein kinases phosphorylate STAT1 and STAT2, forming the heterodimer.
  4. The heterodimer binds with the third cytoplasmic protein (ISGF3G) to form the ISGF3 transcription factor.
  5. ISGF3 then moves into the nucleus and activates transcription by binding to short DNA sequences called IFN-stimulated response elements.
  6. Gene product drive cells into virus-resistant state.
26
Q

What does STAT1 do based on knock out results?

A

Mediate the IFN-dependent stimulation of the antiviral state.

Without STAT1, mice lack innate immunity.

27
Q

What does STAT2 do based on knock out results?

A

Mice knockouts show various defects in immune response, including altered responses to IFNs.

28
Q

What does STAT3 do based on knock out results?

A

Induces expression of liver proteins on the acute phase response. Also responds to leptin and IL-6.

Mice knockouts fail to develop in utero, they are blocked even before gastrulation, and seem not even to form mesoderm.

Did a conditional knockout, defect only occurs in bone marrow, and allowed the normal development to occur but mice didn’t respond to G-CSF which usually stimulates neutrophils production (part of immune response) in bone marrow.

29
Q

What does STAT4 do based on knock out results?

A

Activated by IL-12 (influences helper T-cell differentiation to IFN-producing Th1 cells).

Knock out mice lack IL-12 responsiveness as expected.

30
Q

STAT5A and STAT5B?

A

Regulate expression of milk proteins in response of mammary tissue to prolactin.

Did not develop normal breast tissue and cannot lactate.

31
Q

STAT6?

A

Activated by IL-4, IL3 which have several immune system effects.

32
Q

What are SOCS proteins?

A

Suppressor of cytokine signalling.

33
Q

How are SOCS proteins produced?

A

Produced via feedback mechanism of cytokine signalling pathway.

34
Q

How to SOCS inhibit cytokine signalling?

A

They have an SH2 domain which acts as a competitive inhibitor and replaces spot of STAT SH2 domains, binding to the pTyr and JAK, blocking access to the STAT.

35
Q

What happens when SOCS1 is knocked out?

A

Develop colorectal carcinomas at a high rate. Is an antioncogene.

36
Q

What happens when SOCS2 is knocked out?

A

Gigantism.

37
Q

What happens when SOCS3 is knocked out?

A

Die as embryos.

38
Q

Can STAT proteins be phosphorylated by other TPKS that are not exclusively cytokines?

A

True.

39
Q

How else can STAT dimers be stabilized?

A

Phosphorylation of a serine rather than Tyr, near STAT C-teriminus.

40
Q

Who would perform this alternative phosphorylation?

A

MAP Kinases, resulting in possible cross talk between the cytokine signalling pathway and the growth factor pathway.

41
Q

What is the common ligand of GPCR and Tyr-phosphorylation of STAT1?

A

Angiotensin.

42
Q

What is allograft rejection?

A

Ability of a normal organism to reject grass of foreign tissue (Organ transplants).

43
Q

What is taken to counter the affects of allograft rejection?

A

Immunosuppressant alternatives.

44
Q

How may we conduct this immunosuppressant?

A

By interfering with the cytokine signalling, using JAK3 (involved in signalling of the immune system), an inhibitor on such protein may act as a good immunosuppressant (no crazy side effects or mutations if knocked out).

45
Q

What was the inhibitor of JAK3 found to be?

A

CP-352,664, with improvements.

46
Q

What is the improved and active in the market JAK3 inhibitor?

A

CP-690,550, prevents graft rejection in mice.

Using to treat autoimmune diseases and rheumatoid arthritis.

CHEMISTRY 4360 MIDTERM (5 decks)

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