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MD2002 > Signal Transduction > Flashcards

Signal Transduction Flashcards

1
Q

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

A

1) By phosphorylation (usually phosphorylated is active state. Can be reverse using phosphatase)
2) By GTP binding (usually GTP bound is active form. Can be reversed using GTP hydrolisation)

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2
Q

Around how many kinases and phosphatases does the human genome code for ?

A

Human genomes encodes ~520 kinases and ~150 phosphatases

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3
Q

What are the main kinds of kinase ?

A

Tyrosine kinase

Serine/threonine kinase

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4
Q

What are the main types of GTP-binding proteins ?

A

Trimeric G proteins

Monomeric GTPases

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5
Q

What is signal transduction ?

A

“Process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, which ultimately results in a cellular response.”

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6
Q

How do G-protein coupled receptors function ?

A

Ligand binding activates associated G-protein –> Activates or inhibits downstream enzyme –> generate an intracellular second message

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7
Q

Describe the general structure of G-protein coupled receptors.

A

7 TM helices (hydrophobic amino acids) that reside in the plasma membrane
Their amino termini on the extracellular face
Their carboxy termini on the cytoplasmic face of the plasma membrane.

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8
Q

Give a specific example of a signal transducing G protein along with what it binds.

A

Trimeric signal-transducing G proteins

Bind either GTP or GDP

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9
Q

What does trimeric mean ?

A

Composed of three different subunits (α, β and γ)

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10
Q

What is the mechanism of action of GPCRs which are coupled with trimeric G proteins ?
How is it deactivated ?

A

ACTIVATION
Binding of the ligand to the receptor changes its conformation –> Receptors binds to the Gα subunit of the protein –> Binding induces conformational changes in Gα –> GDP is displaced and GTP is bound –> Gα dissociates from Gβγ –> Ligand dissociates from receptor and Gα binds to effector which activates it

DEACTIVATION
Hydrolysis of GTP to GDP causes Gα to dissociates from effector and reassociate with Gβγ

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11
Q

Is the activation of GPCRs which are coupled with trimeric G proteins short or long lived ? Why ?

A

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

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12
Q

Which receptor can be coupled with Gα ?

A

Glucagon receptor

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13
Q

What are the roles of the GPCRs, G-protein, and adenylate cyclase ?

A

GPCRs: Receptor
G-protein: transducer
Adenylate cyclase: Amplifier (generates large amounts of a second messenger)

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14
Q

What are the ‘main’ types of Gα proteins ? What is their role ?

A

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

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15
Q

True or False: All GPCRs exhibit preferential association with a particular G protein (or subset of G proteins).

A

True

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16
Q

How many types of Gα, Gβ and Gγ proteins are there in total ?
Hence how may possible β γ combinations are possible ?

A

20 Gα
6 Gβ
12 Gγ

72 β γ possible combinations

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17
Q

What are Phospholipase C isoforms ?

A

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

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18
Q

Are all domains between different phospholipids C isoforms different ?

A

Some domains are common (catalytic, membrane localisation),

Some domains are unique (regulatory)

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19
Q

Are the different phospholipid C isoforms activated by the same pathways ? What are some of the pathways which can activate these phospholipid C isoforms ?

A 
No. 
GPCR activation (Gαq), Kinases (possibly ↑Ca2+), Receptor tyrosine kinases
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20
Q

What are the Calcium concentrations of the cell when resting and when activated ?

A

Resting calcium concentration = ~100 nM

Activated calcium concentration = 0.5-1 μM

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21
Q

What factors does the cellular response to increased Calcium depend on ?

A

Cellular response depends upon duration of the signal and on the cell involved

22
Q

Where is the Calcium involved in Calcium signalling derived from ?

A

Calcium can enter from intracellular stores (e.g. ER) or from outside the cell via calcium channels

23
Q

How does Calcium get into the cytosol ? How does it get out of it ?

A

Gets in through channels which may be receptor or voltage operated.
May exit via other channels present in plasma or organelle membranes

24
Q

Give an example of a biological process triggered by Calcium signalling.

A

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

25
Q

How many isoforms does the PKC have ?

A

At least 12

26
Q

Where in the cell is PKC located at rest, and during activation ?

A
  • At rest: Most are present as catalytically inactive, soluble proteins in the cytoplasm.
  • 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+.
27
Q

What is the mechanism of action of PKC once it has been activated by the membrane-associated DAG and/or Ca2+ ?

A

Phosphorylates a wide variety of substrate proteins on serine and threonine residues.

28
Q

Is PKC action short or long-lived ?

A

May be both.

1) Usually short-lived (if substrate is in the cytoplasm)
2) 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. May also indirectly alter gene expression by phosphorylating other molecules which will cause transcription to occur (hence more permanent action).

29
Q

Which of the four main kinds of receptors (ligand-gated, GPCR, Kinase-linked (=enzyme-linked), Nuclear receptor) is β2 adrenergic receptor ?

A

GPCR

30
Q

What is the cellular effect of binding of adrenalin to the β2 adrenergic receptor ?

A

FIGHT OR FLIGHT RESPONSE

  • release of glucose and fatty acids from liver/fat cells
  • increased contraction of cardiac muscle
31
Q

What is the mechanism through which binding of adrenalin to the β2 adrenergic receptor brings about cellular response ?

A

Binding of adrenalin to β2 adrenergic receptor increases the intracellular concentration of cAMP (cyclic AMP) as receptor couples to Gs –> increased cAMP activate the cAMP-dependent protein kinase, PKA –> the catalytic subunits of PKA can phosphorylate substrates on serine or threonine residues and thereby result in cellular change

(PKA has 4 subunits, 2 regulatory and 2 catalytic. Regulator subunits have binding cites for cAMP so when cAMP concentration is high, binding happens, conformation change occurs, and the 2 catalytic subunits dissociate from the double regulatory subunits (the latters are still bound). Active sites of the C subunits become accessible to downstream substrates)

32
Q

Where is cAMP synthesised/degraded ? Using what enzymes ?

A

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

cAMP is degraded by the enzyme cAMP phosphodiesterase

33
Q

Which molecules are responsible for the amplification effect resulting from signal transduction ?

A

Enzymes

34
Q

Where are the substrates of PKA found in the cell ?

A

In the membrane, cytoplasm and the nucleus.

35
Q

Give an example of a substrate of PKA in the nucleus and state its active and inactive form ?

What is the effect of PKA phosphorylation of this substrate ?

A

cAMP response element binding protein (CREB)(transcription factor)
CREB unphosphorylated = inactive
CREB phosphorylated = activate

CREB, binds to this “cAMP response elements (CREs)” in their promoter and activates transcription of downstream genes.

36
Q

What is the function of Cholera Toxin ?

A

Enters intestinal epithelial cells to stimulate Gαs, which in turns activates adenylate cyclase, thereby increasing the concentration of cAMP (excessive production)

37
Q

How is Cholera Toxin activated to enter intestinal epithelial cells to stimulate Gαs ?

A

After cleavage (since it is originally an oligomeric complex)

38
Q

What is the result of increased concentration of cAMP due to Cholera Toxin ?

A

Results in a release of water and ions including Na+, K+, Cl- and HCO3- into the lumen of the small intestine

= rapid fluid loss and dehydration

39
Q

What molecule has the reverse effect of Cholera Toxin ? What exactly does it do ?

A

Pertussis toxin

Inhibits Gαi to increase cAMP production in lung epithelia

40
Q

Give an example of molecule which can activate a Receptor Tyrosine Kinases, and state the end goal of this activation.

A

Insulin-like growth factors activate RTKs to control cell proliferation

41
Q

Describe the general path following Receptor Tyrosine Kinases (RTKs) activation.

A

Usually RTKs monomeric when inactive
Dimeric signalling molecule binds to receptors at the same time, and activates them
When the receptor is activated, catalytic subunits of the receptors become activated and phosphorylate themselves.
Adaptor protein is bound to activated RTK, GTP-ase-activating protein is bound to adaptor protein.
GTP-ase activating protein activates GTP-ase (in inactive form, bound to GDP, which therefore dissociates. GTP binds instead)

42
Q

What is an example of GTPase involved in signal transduction ? What is their role ?

A 
Ras superfamily (Rho, Rap, Rab, Arf etc)
Regulate cellular processes: proliferation, cytoskeletal dynamics, membrane trafficking/vesicular transport
43
Q

How may GTPases be damaged ?

A

By clostridial cytotoxins (affecting Rac/Rho subfamily)

Due to a mutation of Ras proteins to a constitutively-active (GTP-bound) form in approximately 20% of human cancers

44
Q

Which molecule is responsible for the activation of the MAPK (mitogen-activated protein kinase) pathway ?

A

Ras

45
Q

Describe the main steps of the MAPK pathway.

A

Ras activate MAP-kinase kinase kinase, which phosphorylates MAP-kinase kinase, which phosphorylates MAP kinase.
MAP kinase may then phosphorylate genes directly OR
phosphorylate protein in the cell to elicit changes in protein activity

46
Q

Which kind of receptor is EGFR (epidermal growth factor receptor) ? How is it activated ?

A

RTK

Activated by TGFα (Transforming growth factor alpha)

47
Q

Describe the EGFR Receptor Pathway.

A

EGFR receptor activates Ras via Grb2/SOS proteins

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

48
Q

How may cancer arise from the EGFR Receptor Pathway ?

A

Mutations in EGFR, Ras and Raf are associated with tumorigenesis
These cause overexpression and/or hyperactivation of the respective proteins

49
Q

Give two examples in which G-protein linked receptor and enzyme-linked receptor signalling pathways are interconnected.

A

Phospholipase C can be activated by either

Sometimes targets proteins/genes can be activated by both pathways

50
Q

True or false: Receptor Tyrosine Kinases are enzyme-linked receptors.

A

True

MD2002 (77 decks)

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