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Semester 2 Year 1 > Signal Transduction > Flashcards

Signal Transduction Flashcards

1
Q

What do many signalling proteins also act as?

A

molecular switches

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2
Q

What are the two common ways to activate/deactivate signalling proteins?

A

By phosphorylation

By GTP binding

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3
Q

How many kinases/phosphatases does the human genome code for?

A

~520
kinases and

~150 phosphatases

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4
Q

What are the two main kinds of kinases?

A
  • tyrosine kinase

- serine/threonine kinase

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5
Q

What are the two types of GTP-binding proteins?

A
  • Trimeric G proteins

- Monomeric GTPases

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6
Q

What process occurs at G-protein coupled receptors (GPCRs)?

A

Ligand binding activates a G-protein which in turn activates or inhibits another protein. Often this is an enzyme that generates a specific second messenger.

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7
Q

How is an intracellular second message generated?

A

Ligand binding to a G protein coupled receptor activates the associated G protein which in turn inhibits / activates a downstream enzyme to generate an intracellular second message. G protein activation and complex formation are part of a cycle.

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8
Q

Describe the structure of a G-protein-coupled receptor?

A

All G-protein coupled receptors have 7 membrane spanning regions with their amino termini on the extracellular face and their carboxy termini on the cytoplasmic face of the plasma membrane.

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9
Q

What can trimeric signal transducing G proteins bind?

A

Many cell-surface receptors are coupled to trimeric signal-transducing G proteins that bind either GTP or GDP

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10
Q

What does trimeric mean?

A

composed of three different subunits (a, b and gamma in G proteins - beta and gamma split off from alpha to activate it)

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11
Q

What is the mechanism of action of a trimeric G protein in a G protein coupled receptor?

A

Binding of the ligand to the receptor changes its conformation, causing it to bind to the G(alpha) protein in such a way that GDP is displaced and GTP is bound.

This triggers G(b+g) dissociation activating downstream pathways.

Activation is short-lived, as GTP bound to G(alpha) hydrolyzes to GDP in seconds, leading to the re-association of Ga with Gbg and inactivation of adenylate cyclase.

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12
Q

What is GTP required for as discovered by Martin Rodbell?

A

GTP is required for the ligand-induced stimulation of adenylate cyclase.

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13
Q

What does the glucagon receptor bind to?

A

Glucagon receptor couples to Gα(small)s

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14
Q

Overall, what does a signal transduction system need?

A

A receptor

A transducer (G-protein) and

An amplifier (adenylate cyclase) that generates large amounts of a second messenger.

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15
Q

What is GPCR structure?

A

Receptors consist of 7 TM helices (hydrophobic amino acids) that reside in the plasma membrane

Interacts with heterotrimeric G protein complex on the extracellular side

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16
Q

What part of GPCR crosses the plasma membrane?

A

The receptor, eg;

β2 adrenergic receptor
7TM receptor

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17
Q

What part of GPCR is the G protein signalling complex?

A

α, β and γ subunits

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18
Q

How many types of G proteins are there?

A

20

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19
Q

What are all the types of G proteins?

A 
(All not greek script is subscript)
Gαq (or Gq) 
Gs 
Gi
G12/13 
Golf 
Gt 
Gβ/γ dimer
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20
Q

What are the important three G protein types and what do they do?

A

Gαq (or Gq) → stimulates phospholipase C
Gs → stimulates adenylate cyclase, increases cAMP
Gi → inhibits adenylate cyclase, decreases cAMP

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21
Q

What does Gαq (or Gq) do?

A

stimulates phospholipase C

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22
Q

What does Gs do?

A

stimulates adenylate cyclase, increases cAMP

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23
Q

What does Gi do?

A

inhibits adenylate cyclase, decreases cAMP

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24
Q

What does G12/13 do?

A

regulates cytoskeleton, cell junctions, movement, stimulates PLC-ε

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25
Q

What does Golf do?

A

activates olfactory receptors

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26
Q

What does Gt do?

A

transduces visual signals with rhodopsin in the retina

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27
Q

What does a Gβ/γ dimer do?

A

→ gate ion channels
→ stimulates PLA2
→ stimulates adenylate cyclase
→ stimulates PLC-β, PLC-ε and PLC-η

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28
Q

How many Gβ’s and Gγ’s are there?

A

6 Gβ’s and 12 Gγ’s

72 combinations

29
Q

What do all GPCRs exhibit?

A

preferential association with a particular G protein

or subset of G proteins

30
Q

What does GPCR stand for?

A

G protein-coupled receptor

31
Q

What are phospholipase C isoforms?

A

Proteins which possess distinct domain structures but catalyse the same reaction
(liberation of IP3 and DAG from PIP2)

Some domains are common (catalytic, membrane localisation),
Some domains are unique (regulatory)

32
Q

How are phospholipase C isoforms activated

A 
Different pathways including 
GPCR activation (Gαq)
Receptor tyrosine kinases
Kinases (possibly ↑Ca2+)
Small GTPases
Fertilisation
↑Ca2+, Gβγ, other mechanisms?
33
Q

What is the normal calcium level found in the cytosol?

A

Trick question bitchboy: cytosolic calcium levels are dynamic

34
Q

How does calcium enter/exit the cytosol?

A

Calcium can enter from intracellular stores or from outside the cell via calcium channels

Channels may be receptor or voltage operated.

Calcium can exit via other channels present in plasma or organelle membranes

35
Q

What is the resting calcium concentration in the cytosol?

A

~100 nM

36
Q

What is the activated calcium concentration in the cytosol?

A

Activated calcium concentration = 0.5-1 μM

37
Q

Why is the activated cytosolic calcium concentration variable?

A

Cellular response depends upon duration of the signal

38
Q

What biological processes can calcium signals trigger

A

Many,
an example:

fertilisation of an egg by a sperm – initial spark by PLC-ζ (zeta) triggers opening of surface calcium channels

Calcium wave triggers start of embryonic development and prevents other sperm from entering the cell

39
Q

How many different isoforms does protein kinase C have?

A

At least 12 probably

40
Q

How are most protein kinase C-s (PKCs) found in the cell

A

Most are present as catalytically inactive, soluble proteins in the cytoplasm

41
Q

What causes the activation of protein kinase C?

A

Rise in cytosolic calcium levels causes PKC to bind to the cytosolic leaflet of the plasma membrane, where it can be activated by the membrane-associated DAG and/or Ca2+.

42
Q

What does activated protein kinase C do?

A

PKC then phosphorylates a wide variety of substrate proteins on serine and threonine residues.

43
Q

What other functions does protein kinase C have?

A

PKC has substrates in the cytoplasm and some isoforms can translocate to the nucleus to phosphorylate nuclear proteins, and can thus function in a transient way or in a more permanent way (gene transcription).

Protein kinase C activation can also function “indirectly” to alter gene expression

44
Q

Provide an example of other types of GPCR signalling

A

Mediates the body’s response to stress/fear (fight or flight!!)

 release of glucose and fatty acids from liver/fat cells
 increased contraction of cardiac muscle

Binding of adrenalin to b2 adrenergic receptor increases the intracellular concentration of cAMP (cyclic AMP) as receptor couples to Gs

cAMP is synthesized within cells from ATP by the enzyme adenylate cyclase

cAMP is degraded by the enzyme cAMP phosphodiesterase

Different receptors utilize a common adenylate cyclase (i.e., each receptor does not have its own intrinsic adenylate cyclase).

45
Q

How does increased cAMP activate the cAMP-dependent protein kinase, PKA?

A

cAMP binds to regulatory subunits bound to catalytic subunits, causing a conformational change which releases the catalytic subunits, thus exposing the catalytic site

46
Q

What does signal transduction do to a signal?

A

It amplifies it

47
Q

What can the catalytic subunit of PKA phosphorylate?

A

substrates on serine or threonine residues

48
Q

Where does PKA have substrates?

A

in the membrane, cytoplasm and the nucleus.

49
Q

What does PKA do in the nucleus?

A

PKA can activate transcription of genes containing cAMP response elements, or CREs in their promoter. A specific transcription factor, the cAMP response element binding protein, CREB, binds to this sequence and activates transcription of downstream genes. When CREB is unphosphorylated, it is inactive; only in its phosphorylated state does CREB activate transcription.

i.e. ligand binding to a cell surface receptor can induce gene expression

50
Q

What is the cholera toxin and what does it do?

A

Oligomeric complex which after cleavage becomes active and enters intestinal epithelial cells to stimulate Gαs

The overstimulation of cAMP production results in a release of water and ions including Na+, K+, Cl- and HCO3- into the lumen of the small intestine

This leads to rapid fluid loss and dehydration

51
Q

What does the pertussis toxin do?

A

Pertussis toxin acts in the reverse manner to cholera for the same effect, inhibiting Gαi to increase cAMP production in lung epithelia

52
Q

Describe the action of receptor tyrosine kinases (RTKs)

A

They are found across the membrane in an inactive state. A signal molecule in the form of a dimer then binds, stimulating kinase activity. As an active receptor tyrosine kinase they bind phosphorylated tyrosine. Intracellular signalling proteins then bind to phosphorylated tyrosines.

Thus, signal is relayed by activating signalling proteins into the cells interior

e.g. Insulin-like growth factors activate RTKs to control cell proliferation

53
Q

How long do GPCRs take to have an effect?

A

Seconds

54
Q

How long do Kinase linked receptors take to have an effect?

A

Hours

55
Q

What are receptor tyrosine kinases an example of?

A

Kinase linked receptors

56
Q

What are the roles a kinase linked receptor can fulfil?

A

Enzyme-linked receptors

Maybe more idk

57
Q

What do Ras proteins do?

A

Regulate cellular processes: proliferation, cytoskeletal dynamics, membrane trafficking/vesicular transport

58
Q

How do Ras proteins do so goddamn much?

A

Ras superfamily contains over 100 members: Rho, Rap, Rab, Arf etc.

59
Q

How are Ras proteins activated?

A

Receptor Tyrosine Kinases activate Ras

(Activates adaptor protein which activates Ras-activating protein which replaces GDP bound to Ras with GTP thus activating it and continuing the signal)

60
Q

What are Ras proteins?

A

GTPases

61
Q

Discuss GTPases and disease

A

Damage to these small GTPase switches can have catastrophic consequences for the cell and the organism.

Several small GTPases of the Rac/Rho subfamily are direct targets for clostridial cytotoxins.

Further, Ras proteins are mutated to a constitutively-active (GTP-bound) form in approximately 20% of human cancers.

62
Q

What do Ras proteins activate?

A

the MAPK (mitogen-activated protein kinase) pathway

63
Q

what does the MAPK (mitogen-activated protein kinase) pathway cause?

A

Changes in protein activity

Changes in gene expression

64
Q

Discuss EGFR pathway and cancer

A

EGFR (epidermal growth factor receptor) is a RTK activated by TGFα (Transforming growth factor alpha)

The receptor activates Ras via Grb2/SOS proteins

Ras activates Raf (kinase), which in turn stimulates gene transcription via other kinases (MEK and ERK).

Mutations in EGFR, Ras and Raf are associated with tumorigenesis

These cause overexpression and/or hyperactivation of the respective proteins

65
Q

What effect does the EGFR receptor pathway have on Ras proteins?

A

The receptor activates Ras via Grb2/SOS proteins

66
Q

What is the EGDR?

A

epidermal growth factor receptor

67
Q

Do signalling pathways interconnect?

A

Hell to the YES

68
Q

Why med?

A

Fuck else to do

Semester 2 Year 1 (82 decks)

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