signal transduction Flashcards
What is “Signal Transduction”?
The process by which a cell converts an extracellular signal into a response.
what is signal transduction used in?
Involved in:
Cell-cell communication
Cell’s response to environment
Intracellular homeostasis (internal communication)
what are the chemical ways cells used to communicate
Autocrine & Paracrine: local signalling
Endocrine system: distant, diffuse target, transported via blood
state the process of cell signalling
signal molecule binds to receptor protein
receptor protein activates intracellular signal molecules
intracellular signal molecules alters target proteins
target proteins create response
what is external message to cell?
Signal
example of a signalling system
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
example of cell membrane receptor?
growth factor receptor
features of cell membrane receptor?
Lipophobic ligand can’t enter cell
Outer surface receptor
Fast response
example of Cytosolic/nuclear recceptors?
steroid hormone receptor
features of Cytosolic/nuclear recceptors?
Lipophilic ligand enters cell
Often regulates gene exprn
Slower response
list the Membrane receptor classes
(1)ligand-gated ion channels
(2)G protein–coupled receptors (GPCRs)
(3)enzyme-linked receptors
(4)nuclear receptors
describe ligand-gated ion channels
ligand binding opens of closes the channel
describe G protein–coupled receptors (GPCRs)
ligand binding to a G protein-coupled receptor opens an ion channel or alters enzyme activity.
describe enzyme-linked receptors
ligand binding to a receptor-enzyme activates the intracellular enzyme.
describe nuclear receptors?
ligand binding to integrin receptors alters the cytoskeleton.
describe cell signal initiation and transduction.
refer to slide 09
what do pathways do to the signal?
Pathways amplify the signal
what happens during enzyme cascade
signal amplification during relay
what are proto-oncogenes
A gene involved in normal cell growth.
what causes growth of cancer cells in reference to proto-oncogenes
Mutations (changes) in a proto-oncogene may cause it to become an oncogene, which can cause the growth of cancer cells
list the different proto-oncogenes
Serine/Threonine Kinases
Raf
Akt
Non-receptor tyrosine kinases
Src (Avian/Rous sarcoma virus)
Abl (Abelson murine leukaemia virus)
GTP-binding proteins
Ras
list 8 ligands which, via receptor binding, signal diverse cellular responses
KGF
PDGF
VEGF
EGF
FGF
IGF
TGF-B
CTGF
DEFINE KGF
keratinocyte growth factor
growth and new keratinocyte generation
DESCRIBE PDGF
Platelet derived growth factor
cell growth, new generation and repair of blood vessels, collagen production
describe the VEGF
Vascular endothelial Growth factor
promotion of angiogensis promotion wound healing.
EGF
epidermal growth factor
promotion of epithelial cell growth, angiogenesis, promotion of wound healing
FGF
fibroablast growth factor
growth factor present in the epithelialization phase of wound healing, keratinocytes cover wound forming.
describe IGF
insulin like growth factor
for cell growth regulation
describe TGF-B
Transforming growth factor- beta
growth and neogenesis of epithelial cells and vascular endothelial cells, promotion wound healing.
CTGF
Connective tissue growth factor
promotes angiogenesis, cartilage regeneration, and platelet adhesion.
STOPPED AT THAT SLIDE
List the signaling downstream effector domains and what they are bind to?
• 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)
Binding of docking proteins is sequence specific. True or false?
True
State where Activated ( phosphorylated) PTKs is bind to in SH2 domains and what they do?
•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
What are the mechanisms for attenuation & termination of RTK activation?
- ligand antagonists
- receptor antagonists
- phosphorylation and dephosphorylation
- receptor endocytosis
- receptor degradation by the ubiquitin- proteasome pathway
How was tyrosine kinases attempted to be blocked?
•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
Where does the ATP binding sites in TKs happens?
ATP binds within a deep cleft formed between the two lobes of the TK domain
The ATP binding site regions in TKs are?
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.
what does Tyrosine kinase inhibitors (TKIs) do?
Bind specifically to kinase domain of TKs
Block substrate phosphorylation
Block subsequent downstream signalling
Apart from the cancer cells, what other cells are targeted in TKIs?
Tumour cells
Endothelial cells in tumour angiogenesis (VEGFRs)
Stromal fibroblasts
what are the development of TKIs in place?
Structure-based drug design
Crystallographic structure information
Combinatorial chemistry and high-throughput screening
TKIs development aims to achieve what?
Greater potency
Greater selectivity
Higher efficacy
Decreased toxicity
ADMET
