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RTK and signal transduction Flashcards

1
Q

what is signal transduction

A

the process by which a cell converts an extracellular signal into a response

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2
Q

what are the types of signal transduction

A
  1. cell to cell communication
  2. cells response to the environment
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3
Q

what are the 2 types of cell to cell communication and explain them

A

intercellular - between cells
intracellular - within the cells

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4
Q

what is an autocrine signalling

A

a chemical messenger that affects the cell that produced it

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5
Q

what is endocrine signalling

A

a chemical signal that affects cells far away from the cell that secreted it - the signalling molecules (i.e hormones) enters the blood stream (long distances)

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6
Q

what is paracrine signalling

A

a chemical signal that affects nearby cells of the cell that secreted it (short distance)

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7
Q

describe the signal pathway

A
  1. signal molecule such as ligand. it is an entity that initiates a signal
  2. it binds to receptor protein that recognises it
  3. once the ligand binds to the receptor, it activates it , causing a pathway of intracellular signally mediators .
  4. this can be a pathway and can involve secondary messengers
  5. then they’ll act on target proteins that are responsible for causing the response
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8
Q

list the examples of ligands

A

amino acids derivatives such as epinephrine, histamine , glucagon
peptides/ protein
small biomolecules such as ATP
steroids, prostaglandins
gases i.e nitric oxide
damaged DNA
odorants, tastants

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9
Q

what are the 2 types of receptor locations

A

cell membrane receptor
cytosolic / nuclear receptor

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10
Q

explain what cell membrane receptors are, and give one example of one

A

> they engage lipophobic (hydrophilic ligands)

> these lipophobic ligands can’t enter the cell because the cell membrane is lipophilic ( phospholipid bilayers)

> so they bind to the surface cell receptors, which creates a cascade of intracellular pathways that is carried out inside the cell

an example: growth factor receptors

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11
Q

explain what the cytosolic / nuclear receptors are

A

> they engage lipophilic ligand (i.e steroids) which has diffused through the cell membrane into the cell

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12
Q

what is the difference in the response of nuclear receptors and cell mebrane receptors

A

cell memb receptors are fast responses while nuclear receptors are slower responses but very powerful.

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13
Q

what are the classes of membrane receptors

A

+ Ligands binding to channels which opens or closes channels

+ Ligand binding to receptor-enzymes which activates an intracellular enzyme

+ Ligand binding to a GPCR (G protein coupled receptor) which opens an ion channel or alters enzyme activity

+Ligand binding to integrin receptors which alters the cytoskeleton

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14
Q

what is GPCR

A

G-protein coupled receptors.
1. GPCR are imbedded in plasma membranes.
2. the receptor portion has 7 transmembrane domain, that loops in and out from the intra and extracellular side.
3. the receptor is connected to a G protein network which consists of 3 sub units [alpha, beta, gamma] - hence the name heterotrimeric G-protein,

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15
Q

what is the role of GPCR in cell signalling

A
  1. the signalling molecule binds to the receptor, causing conformational change within the trimeric protein subunit of the G Protein.
  2. the gamma and the beta subunit stays part of the plasma membrane, but the alpha disconnects

3.on the alpha sub unit, you get the conversion of GDP to GTP. when the GTP is on the alpha subunit of the G-protein, you get a GTP-bound alpha subunit

  1. this alpha subunit is now active. when it is active, it can act be either Gs or Gi

4.1 G sub S (GS)
> Gs activate adenyl cyclase which converts ATP into CAMP
> CAMP activates protein kinase A (PKA)
> PKA can carry out secondary messenger effects

4.2 G sub I (Gi)
> GI inhibits adenyl cyclase which never allows for ATP to CAMP, which never allows for PKA to be activated

  1. the alpha subunit can also have a different mechanism that’s not Gs or GI. instead, it acts as Gq
  2. Gq activates phospholipase C which activates the conversion of PIP2 to IP3 and DAG.

6.1 IP3 causes a release of Ca2+ from endoplasmic reticulum

6.2 DAG activates Protein Kinase C (PKc)

6.3 both of these have further downstream effects, particularly ca2+ which activates a whole host of enzymes.

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16
Q

outline the steps of signal transduction

A
  1. ligand binds to the receptor which receives the signals
  2. this receptor either directly or through proteins activate amplifier enzymes which then act on secondary messengers
  3. these messengers propagate the signal which activate important proteins such as kinases which lead to phosphorylated protein
  4. or lead to increased Ca2+ which then leads to calcium bind protein
  5. this brings about a cell response
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17
Q

why is signal transduction important

A

+ they amplify the signal.
+ one ligand binding to 1 receptor doesn’t have much effect, however when it acts on multiple downstream molecules, it causes an amplification

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18
Q

what does multiple pathways in a signal transduction allow

A

for control due to multiple signals that all dont work at the same time

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19
Q

how does signal transduction relate to cancer

A

many signalling proteins are proto oncogenes.

these proteins have normal functions in the cell, but when mutated, they can turn a normal cell into an oncogene

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20
Q

what are kinases

A

enzymes that phosphorylates substrate

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21
Q

give the examples of protooncogenes signalling proteins

A

> serine / threonine kinases]
GTP binding proteins
non receptor tyrosine kinases

22
Q

what are serine / threonine kinases and give an example

A

enzymes that catalyse the transfer of a phosphate group from ATP to the OH groups of the amino acids serine and threonine

i.e RAF, AKT

23
Q

give examples of GTP binding proteins

A

RAS

24
Q

give examples of non receptor tyrosine kinases

A

Src (Avian/Rous sarcoma virus)
Abl (Abelson murine leukaemia virus)

25
Q

what are RTK

A

They are RECEPTOR TYROSINE KINASES
= they are enzymes that specifically phosphorylate at the tyrosine receptor (tyrosine is the substrate)

26
Q

what are RTKs also ?

A

they are growth factor receptors (aka enzyme linked receptors)

27
Q

what are growth factors

A

a secreted biologically active molecule that can affect the growth of cells.

28
Q

what are growth factors receptors (GFR)

A

receptors that bind to growth factors (GF)

29
Q

list the 8 examples of Growth Factors [GFs], and their role

A
  1. Epidermal growth factor (EGF) = promotion of epithelial cell growth, angiogenesis { formation of new blood vessels}and wound healing
  2. Keratinocyte growth factor (KGF)
    = growth and new keratinocytes generation
  3. Platelet derived GF (PDGF) = cell growth, new generation and repair of blood vessels, collagen production
  4. Vascular endothelial growth factor (VEGF) = promotion of angiogenesis, promotion of wound healing
  5. Fibroblast Growth factor (FBF) = growth factor present in the epithelisation phase of wound healing, keratinocytes cover the wound, forming the epithelium
  6. Insulin like growth factor (IGF) = cell growth regulation
  7. Connective tissue growth factor (CTGF) promotes angiogenesis, cartilage regeneration and platelet adhesion.
  8. Transforming growth factor beta (TGF-B) = growth and neogenesis of epithelial cells and vascular endothelial cells, promotion of wound healing
30
Q

what’s the difference between a viral oncogene egfr and a normal egfr

A

oncogenic egfr have no of the inhibitory domain of ligand binding domain or truncated carboxy terminus. without these, the EGFR stays activated.

In normal egfr, there is a ligand binding site and a truncated carboxy terminus that when ligand binds, it inactivates.

31
Q

what is phosphorylation

A

a phosphoryl group (phosphate), donated by ATP, is transferred to an acceptor protein. the reaction is catalysed by a protein kinase.

protein kinase transfers the terminal phosphate of ATP to a hydroxyl group on a protein (+ve switch )
> > it’s a dehydration reaction

Opposite direction: a protein phosphate catalyses removal of the Pi by hydrolysis (- ve switch)

32
Q

what are thre 3 amino acids that are receptive to being phosphorylated

A

serine, threorine, and tyrosine

33
Q

what are EGFR/ HER-1 / ErbB-1

A

these are all interchangeable. they are closely related to rtks.

HER: Human Epidermal growth factor Receptor
ERB: ErbB1 (epidermal growth factor receptor)

34
Q

EXPLAINS WHAT HAPPENS IN CANCER ErbB1

A

ErbB1 is a protein found on certain types of cells that bind to EGF. The ErbB1 protein is involved in cell signalling pathways that control cell division and survival. When mutations occur in the EGFR gene, it causes ErbB1 proteins to be made in higher-than-normal amounts on some types of cancer cells. This causes cancer cells to divide more rapidly. Drugs that block ErbB1 are being used in the treatment of some types of cancer. F

35
Q

how are RTKs activated for signal transduction

A
  1. 2 separate growth factors bind to 2 separate RTK receptors
  2. this causes them to form dimers through dimerization
  3. the dimers phosphorylate each other’s tyrosine residues in a process called transphosphorylation. so basically one tyrosine will take a phosphate FROM ATP which is turned to ADP. this is catalysed by the kinases.
  4. these are then new binding sites for SH2 domains (src homology 2) proteins , allowing different molecules to bind and to be phosphorylated.

phosphorylation causes conformational change exposing the new binding sites

36
Q

How does activation of RTK amplify signals affects cells

A

it enhances TK catalytic activity
also exposes docking sites for SH2 domain proteins

37
Q

how can activated RTK affect the cell (in regards to RAS)

A

there can be multiple cellular responses from one dimerization

+ RAS is usually inactive when it has GDP bound to it
+ RAS could bind to SH2 domain protein , and become activated when the GDP is phosphorylated to GTP
+ RAS undergoes this pathway when it goes to RAF (controlled by Map-KKK) which will go to MEK (controlled by MapKK) which will go to ERK ( controlled by MAPk)

38
Q

what do the kinases in the pathway do

A

they amplify the initial signal as you go down, leading to a very strong output

39
Q

which SH2 domains do activated RTKs bind to

A

> non receptor TKs such as Src
phospholipase Cy (PLCy)
phosphatidylinositol 3’ kinase (PI 3-kinase)
SHP2 tyrosine phosphatase
GTPase activating protein
Nck2

40
Q

what do PLCy do

A

catalyses the breakdown of the lipid, phosphatidylinositol (4,5) bisphosphate (PI4,5P2), into two second messengers: IP3 & DAG

41
Q

what do PI 3- kinase do

A

Phosphorylates PI4,5P2 to generate the second messenger PI3,4,5P3

42
Q

what do SHP2 tyrosine phosphatase do

A

dephosphorylates pY residues on RTKs

43
Q

what do GTPase activating protein

A

inactivates p21Ras-GTP

44
Q

what do Nck2 do

A

regulates the cytoskeleton

45
Q

what are tyrosine kinase inhibitors (TKIs)

A

these are ligands / molecules that inhibit RTKs activation by either attenuation or termination.

Attenuation = the reduction of the amplitude of a signal

they have the potential to cause cancer, and have been shown to be overexpressed in cancer cells

46
Q

outline the types of TKIs

A

> Ligand antagonists so ligand can’t bind to receptor
Receptor antagonists - so ligand can’t bind
Phosphorylation & dephosphorylation focus for developing anticancer drugs
Receptor endocytosis - receptor swallowed up by the cell
Receptor degradation by the ubiquitin - proteasome pathway

47
Q

which TKIs are the are seen as the most useful

A

ATP competitive inhibitors

48
Q

how do ATP bind to RTKs

A

Kinases use atp to phosphorylate substrates and must bind atp first through their atp binding site
- ATP binds within a deep cleft formed between the two lobes of the TK domain.
- new drugs are trying to stop the ATP from binding

49
Q

ATP competitive inhibitor= which regions of the atp binding site in TKs can be blocked

A
  1. the adenine region - there are 2 key H bonds formed by the interaction of N-1 an N -6 amino group of the adenine rings. may potent inhibitors target one of these bonds
  2. the sugar region
  3. hydrophobic pocket - important role in inhibitor selectivity
  4. hydrophobic channel - not used by atp but can be exploited for inhibitor specificity,
50
Q

how are TKIs develope

A
  • structured based drug design
  • crystallographic structure information
  • combinational chemistry and high throughput screening
51
Q

give an example of a TKI

A

gefitinib - binds to atp binding site of the kinase

52
Q

what are the prospect of tki development

A
  • greater potency
  • greater selectivity
  • higher efficacy
  • decreased toxicity
  • ADMET

O cancer (8 decks)

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