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personalised medicine and cancer > signal transduction > Flashcards

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 is signal transduction used in?

A

Involved in:
Cell-cell communication
Cell’s response to environment
Intracellular homeostasis (internal communication)

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3
Q

what are the chemical ways cells used to communicate

A

Autocrine & Paracrine: local signalling

Endocrine system: distant, diffuse target, transported via blood

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4
Q

state the process of cell signalling

A

signal molecule binds to receptor protein

receptor protein activates intracellular signal molecules

intracellular signal molecules alters target proteins

target proteins create response

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5
Q

what is external message to cell?

A

Signal

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6
Q

example of a signalling system

A

ligand–receptor interaction:

Peptides/proteins, e.g. growth factors, vasoconstrictors

Amino acid derivatives - epinephrine, histamine

Other small biomolecules - ATP

Steroids, prostaglandins

Gases e.g. nitric oxide (NO)

Photons

Damaged DNA

Odorants, tastants

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7
Q

example of cell membrane receptor?

A

growth factor receptor

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8
Q

features of cell membrane receptor?

A

Lipophobic ligand can’t enter cell
Outer surface receptor
Fast response

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9
Q

example of Cytosolic/nuclear recceptors?

A

steroid hormone receptor

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10
Q

features of Cytosolic/nuclear recceptors?

A

Lipophilic ligand enters cell
Often regulates gene exprn
Slower response

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11
Q

list the Membrane receptor classes

A

(1)ligand-gated ion channels

(2)G protein–coupled receptors (GPCRs)

(3)enzyme-linked receptors

(4)nuclear receptors

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12
Q

describe ligand-gated ion channels

A

ligand binding opens of closes the channel

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13
Q

describe G protein–coupled receptors (GPCRs)

A

ligand binding to a G protein-coupled receptor opens an ion channel or alters enzyme activity.

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14
Q

describe enzyme-linked receptors

A

ligand binding to a receptor-enzyme activates the intracellular enzyme.

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15
Q

describe nuclear receptors?

A

ligand binding to integrin receptors alters the cytoskeleton.

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16
Q

describe cell signal initiation and transduction.

A

refer to slide 09

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17
Q

what do pathways do to the signal?

A

Pathways amplify the signal

18
Q

what happens during enzyme cascade

A

signal amplification during relay

19
Q

what are proto-oncogenes

A

A gene involved in normal cell growth.

20
Q

what causes growth of cancer cells in reference to proto-oncogenes

A

Mutations (changes) in a proto-oncogene may cause it to become an oncogene, which can cause the growth of cancer cells

21
Q

list the different proto-oncogenes

A

Serine/Threonine Kinases
Raf
Akt

Non-receptor tyrosine kinases
Src (Avian/Rous sarcoma virus)
Abl (Abelson murine leukaemia virus)

GTP-binding proteins
Ras

22
Q

list 8 ligands which, via receptor binding, signal diverse cellular responses

A

KGF

PDGF

VEGF

EGF

FGF

IGF

TGF-B

CTGF

23
Q

DEFINE KGF

A

keratinocyte growth factor

growth and new keratinocyte generation

24
Q

DESCRIBE PDGF

A

Platelet derived growth factor

cell growth, new generation and repair of blood vessels, collagen production

25
Q

describe the VEGF

A

Vascular endothelial Growth factor
promotion of angiogensis promotion wound healing.

26
Q

EGF

A

epidermal growth factor

promotion of epithelial cell growth, angiogenesis, promotion of wound healing

27
Q

FGF

A

fibroablast growth factor

growth factor present in the epithelialization phase of wound healing, keratinocytes cover wound forming.

28
Q

describe IGF

A

insulin like growth factor

for cell growth regulation

29
Q

describe TGF-B

A

Transforming growth factor- beta

growth and neogenesis of epithelial cells and vascular endothelial cells, promotion wound healing.

30
Q

CTGF

A

Connective tissue growth factor

promotes angiogenesis, cartilage regeneration, and platelet adhesion.

31
Q

STOPPED AT THAT SLIDE

A
32
Q

List the signaling downstream effector domains and what they are bind to?

A

• SH2 and PTB domains : bind to tyrosine phosphorylated sites
• SH3 and WW domains : bind to proline - rich sequences
• PDZ domains : bind to hydrophobic residues at target protein C- termini
• PH domains - bind to different phosphoinosites
• FYVE domains : bind to phosphatidylinositol 3- phosphate (in membrane)

33
Q

Binding of docking proteins is sequence specific. True or false?

A

True

34
Q

State where Activated ( phosphorylated) PTKs is bind to in SH2 domains and what they do?

A

•Non-receptor TKs such as Src
•Phospholipase Cg (PLCg)
- catalyses the breakdown of the lipid, phosphatidylinositol (4,5) bisphosphate (PI4,5P2), into two second messengers: IP3 & DAG

•Phosphatidylinositol 3’ kinase (PI 3-kinase)
- Phosphorylates PI4,5P2 to generate the second messenger PI3,4,5P3

•SHP2 tyrosine phosphatase
- dephosphorylates pY residues on RTKs

•GTPase activating protein
- inactivates p21Ras-GTP

•Nck2
- regulates the cytoskeleton

35
Q

What are the mechanisms for attenuation & termination of RTK activation?

A
  • ligand antagonists
  • receptor antagonists
  • phosphorylation and dephosphorylation
  • receptor endocytosis
  • receptor degradation by the ubiquitin- proteasome pathway
36
Q

How was tyrosine kinases attempted to be blocked?

A

•Late 1980 - low molecular weight tyrosine Kinase inhibitors (TKIs) was developed but not very good
•it was difficult for low molecular wt compounds to interfere with ligand binding or protein substrate
• failed to create non competitive kinase or allosteric inhibitors
• ATP competitive inhibitors appeared as target choice

37
Q

Where does the ATP binding sites in TKs happens?

A

ATP binds within a deep cleft formed between the two lobes of the TK domain

38
Q

The ATP binding site regions in TKs are?

A

Adenine region – Two key H bonds formed by interaction of N-1 and N-6 amino group of the adenine ring.
Many potent inhibitors target one of these H bonds.
Sugar region – a hydrophilic region, except a few e.g. EGFR.
Hydrophobic pocket –Important role in inhibitor selectivity.
Hydrophobic channel – not used by ATP
May be exploited for inhibitor specificity.
Phosphate binding region – Used for improving inhibitor selectivity.

39
Q

what does Tyrosine kinase inhibitors (TKIs) do?

A

Bind specifically to kinase domain of TKs
Block substrate phosphorylation
Block subsequent downstream signalling

40
Q

Apart from the cancer cells, what other cells are targeted in TKIs?

A

Tumour cells
Endothelial cells in tumour angiogenesis (VEGFRs)
Stromal fibroblasts

41
Q

what are the development of TKIs in place?

A

Structure-based drug design
Crystallographic structure information
Combinatorial chemistry and high-throughput screening

42
Q

TKIs development aims to achieve what?

A

Greater potency
Greater selectivity
Higher efficacy
Decreased toxicity
ADMET

personalised medicine and cancer (16 decks)

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