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BGM2002 CS > L2 - Introduction to cell signalling II > Flashcards

L2 - Introduction to cell signalling II Flashcards

1
Q

What are the 3 general strategies used to transfer information across the PM?

A

Intracellular receptors
• Membrane-permeable small hydrophobic signals diffuse passively

Ion-coupled channels
• Signals bind to & regulate opening of membrane channels

Transmembrane receptors
• Signals bind to TM receptors - activation of intracellular enzymes

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2
Q

Intracellular receptors

A

Bound by small hydrophobic molecules that can pass through the hydrophobic membrane

Bind to nuclear receptors

Cellular response = relatively slow

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3
Q

How do steroid hormones work?

A
  1. Formation of a complex ligand-receptor
  2. Upon binding of the ligand, receptor becomes active
  3. Hormone-receptor complex translocates into the nucleus where it acts as a transcription factor turning on testosterone-responsive genes

Intracellular receptors

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4
Q

What can you call ion-coupled channels?

A

Ligand-gated ion channels
Ion-coupled channels
Ion-channel-coupled receptors

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5
Q

What are ligand-gated ion channels?

A

Transmembrane pores formed of multiple protein subunits

Key role in synaptic signalling: covert chemical signal (neurotransmitter) into electric signal (ion flow)

Cellular response = very rapid (milliseconds)

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6
Q

How do ligand-gated ion channels work?

A
  1. Ligand binds to extracellular part of channel
  2. Induces a conformational change of the receptor – opens the ion channels
  3. Results in a flow of small molecules such as ions across the cell membrane
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7
Q

Cell surface receptors

A

Most diverse & most commonly used
Most signal molecules are large and/or hydrophilic & cannot cross the PM so must bind to receptors

Each cell expresses a repertoire of TM receptors

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8
Q

What are transmembrane receptors?

A

Sensors that detect extracellular stimuli – act like a molecular switch

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9
Q

Cell surface receptor structure

A

EC ligand-binding site: highly specific & sensitive

1 or more hydrophobic transmembrane domains

IC portion of receptor coupled to downstream signalling

Receptor transduces EC signal into IC signalling cascade

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10
Q

2 common strategies used to transfer signals in cell surface receptors

A

Receptor conformational changes

Receptor clustering

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11
Q

3 main classes of transmembrane receptors

A

GPCR

Enzyme-linked receptor

Cytokine receptor

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12
Q

What are GPCRs?

A

7 transmembrane protein

Coupled with large protein G

Largest family of cell surface receptors in eukaryotes

Many functions: smell, taste, sight, endocrine function, neuronal communication

Many drugs act through GPCRs

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13
Q

What are enzyme-linked receptors?

A

The receptor has catalytic activity

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14
Q

What are cytokine receptors?

A

Receptor has no catalytic activity

Coupled to an intracellular enzyme

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15
Q

Process of GPCRs

A

Binding of ligand to EC domain induces a conformational change of receptor allowing its cytosolic domain to bind to & activate the G protein

G protein acts as an on/off switch: if GTP is bound to the G protein it is active

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16
Q

What are G proteins composed of?

A

3 subunits
• Alpha - binds GDP & GTP
• Beta & Gamma

2 lipid anchors

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17
Q

Activation of G proteins

A
  1. G protein is inactive & binds GDP
  2. GPCR binds its ligand & induces a change of conformation
  3. Alpha subunit binds GTP instead of GDP & becomes active
  4. Alpha subunit dissociates from beta & gamma & migrates to target protein
  5. Target protein activated
  6. 2nd messenger produced
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18
Q

Deactivation of G proteins

A
  1. Alpha subunit hydrolyses GTP by GTPase activity
  2. Alpha dissociates from target protein
  3. Alpha re-associates with beta & gamma
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19
Q

Example of GPCR signalling

Epinephrine receptor

A

Response to stress

Adenylyl cyclase produces cAMP which is the second messenger

Acts on multiple effectors

Allows person to run faster

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20
Q

Abnormal G-protein signalling can be caused by…

A

Cholera bacterial toxins

Gene mutations

Single nucleotide polymorphisms

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21
Q

How do cholera bacterial toxins cause abnormal G-protein signalling?

A

Binds to alpha subunit  inactivates GTPase activity

Leads to defective signal termination with persistent elevated levels of cAMP & effector activity (loss of salt from epithelial cells of the intestine)

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22
Q

What types of gene mutations cause abnormal G-protein signalling?

A

Loss of function
• Signalling in response to the corresponding agonist
• Receptor becomes resistant to signal

Gain of function
• Leads to constitutive, agonist-independent activation of signalling

Mis-folding of GPCR
• Receptor retains its function but located in parts of cell where function in inappropriate

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23
Q

How do single nucleotide polymorphisms cause abnormal G-protein signalling?

A

Impact of SNPs on individual variations in response to drug as GPCRs mediate the therapeutic effects of more than 30% of FDA-approved drugs

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24
Q

What are receptor tyrosine kinases (RTKs)?

A

Single transmembrane span receptors
An enzyme coupled receptor

Extracellular side – ligand binding site
Cytoplasmic side – Tyr kinase domain & tyrosine’s

2 forms:
– Monomeric inactive
– Dimeric active

A RTK can trigger multiple signal transduction pathways at once

Autophosphorylation increases the catalytic efficiency of the receptor & provides binding sites for the assembly of downstream signalling complexes

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25
RTK activation steps
1. A bivalent ligand binds simultaneously to 2 RTKs inducing a dimerisation of monomeric RTKs 2. Dimerisation activates Tyr kinase activity 3. Autophosphorylation of Tyr domains 4. RTKs interact with & activate proteins 5. Cellular response
26
Structure of RTKs
EC domain • Highly variable binding • Recognition of various signals TM domain • Small • Hydrophobic IC domain • Common: Tyr kinase domain • Some kinase domains are interrupted by inserts
27
What is the EGF receptor?
Receptor for Epidermal Growth Factor (EGF) Member of the ErbB family involved in angiogenesis, apoptosis, cell proliferation & metastasis
28
Activation of the EGF-R
Activation of the EGF-R by EGF Phosphorylation of tyrosine of cytoplasmic proteins Signals to the cell to proliferate & grow
29
Deregulation of EGF-R in cancer
Don’t need a ligand to activate the receptor in cancer cells ``` 1 or more members of the family of EGRF genes are overexpressed or deregulated in most epithelial tumours by: – Activating mutation – Increase gene copy number – Overexpression – Truncation of receptor EC domain ```
30
Cytokine receptors: JAK-STAT signalling
Large family of receptors Activated by cytokines (interferon & interleukins) or growth factors (prolactine & EPO) Control synthesis & release of inflammatory mediators Receptor has no catalytic activity but associated with kinase
31
What are the 3 main components of the JAK-STAT signalling pathway?
Receptor Janus Kinases (JAK) STATs
32
Receptors in the JAK-STAT signalling pathway
Binds to cytokine or growth factor Receptor forms a dimer
33
Janus Kinases (JAK) in the JAK-STAT signalling pathway
‘Just Another Kinase’ Dimeric receptors associate with Janus Tyrosine Kinases (JAKs) & activate JAKs which: • Cross phosphorylate each other • Phosphorylate & activate R • PO4- creates a docking site for SH2 domains of transcription regulators STATs • JAKs phosphorylate & activate STATs
34
STATs in the JAK-STAT signalling pathway
Transcription regulators STAT: Signal Transducers & Activators of Transcription Dissociate from the receptor & dimerise Dimer migrates to the nucleus where it binds to promoter region & activates transcription of target genes
35
JAK-STAT signalling: example of leptin What is leptin?
Satiety hormone – feeling of being full Is produced by adipose (fat) tissue Reduces food intake, controls metabolism & body weight
36
JAK-STAT signalling: example of leptin The leptin receptor
Cytokine receptor in brain satiety centre Binding of leptin to its receptor activates JAK proteins that phosphorylate tyrosine residues on the leptin receptor, allowing for the recruitment & phosphorylation of STATs STAT proteins dimerise, translocate to the nucleus & act as transcription factors stimulating expression of genes that inhibit appetite
37
Feedback & adaptation at receptor level
Receptor sequestration Receptor down regulation Receptor inactivation Inactivation of signalling protein Production of inhibitory protein
38
Intracellular receptors Response time & effects
HOURS Alter gene transcription & protein expression
39
Ligand gated ion channels Response time & effects
MILLISECONDS Alter membrane potential
40
GPCRs Response time & effects
SECONDS Can mediate 2nd messengers or can directly activate the ion channels
41
Enzyme-linked receptors / cytokine receptors Response time & effects
HOURS Alter gene transcription & protein expression
42
What is transduction?
Signal relay, amplification & integration Requires transducer molecules
43
Transducer molecules
Signalling proteins • Kinases, Phosphatases, GTPases, Adaptors Second messengers • cAMP & cGMP, Lipids, Calcium, NO Often act as molecular switches
44
Signal transduction cascade
``` Multistep process during which transducers: • Relay • Transduce • Amplify • Integrate • Regulate ```
45
Signal transduction cascade TRANSDUCTION
At each step, signal transduced into a different form, commonly protein conformational change
46
Signal transduction cascade AMPLIFICATION
Signal amplified by activating multiple copies of next component in pathway
47
Signal transduction cascade INTEGRATION
Coordinate, distribute, regulate signal Allow fine tuning of the response & contribute to response specificity
48
Signal transduction cascade REGULATION
Many signalling pathways are regulated by post-translational modifications Phosphorylation, ubiquitination & acetylation
49
Phosphorylation cascade
Reversible molecular switches 1. Relay molecule activates kinase 1 2. Active kinase adds phosphate to next kinase / effector in line, activating or inhibiting it 3. Phosphatase removes PO4-, deactivating the kinase which can be reused – no need for protein synthesis 4. Signal is amplified at each stage
50
Adaptor proteins
Have no intrinsic enzymatic activity Usually contain several protein-binding domains or modules These modules or motifs mediate intermolecular interactions between receptors & specific target proteins
51
How do adaptor proteins mediate intermolecular interactions between receptors & specific target proteins?
Act as docking proteins that link receptors with other effector proteins Scaffold the organisation of large protein complexes between protein-binding partners Dictate: • Specificity of interactions between binding partners • Subcellular localisation of binding partners Integrate signals from different pathways (cross-talks) & coordinate responses Adaptor proteins regulate cell signalling in a spatial & temporal manner
52
Adaptor protein Grb2 recruitment to EGFR-phospho-Tyr activates Ras & MAPK signalling cascade cascade in response to mitogens
1. EGF binds to the receptor activating TK 2. Autophosphorylation of the receptor 3. SH2 binds phosphorylated tyrosine 4. Sos binds SH2 by SH3 & converts GDP to GTP on Ras to activate it 5. Ras phosphorylates RAF 6. RAF phosphorylates MEK 7. MEK phosphorylates MAP kinase which causes the response
53
What are second messengers?
Chemical relays from plasma membrane to cytoplasm - short lived Small, non-protein, water-soluble molecules or ions Greatly amplify the strength of a signal
54
2nd messenger information is encoded by local concentrations
Elevated concentration  triggers rapid alteration of activity of cellular enzymes Removed or degraded  terminates cellular response
55
What are the 3 basic types of 2nd messenger molecules?
Hydrophobic molecules: membrane-associated Hydrophilic molecules: water-soluble molecules in cytosol Gases: can diffuse through cytosol & across membrane
56
cAMP signalling pathway
1. Activation of GPCRs by hormone 2. G-protein (G-alpha-stimulatory) activates adenylyl cyclase 3. AC catalyses cAMP synthesis from ATP 4. cAMP binds PKA regulatory subunits (Protein Kinase A – cAMP-dependent PK) 5. Dissociation from the catalytic subunits Catalytic subunits of PKA: • FAST response: PKA-C phosphorylates enzyme in the cytoplasm (eg. glycogen phosphorylase) • SLOW response: PKA-C enters the nucleus & phosphorylates transcription factors such as CREBP (cAMP response element binding protein). CREBP binds to promoters (CRE) & turns on gene expression
57
Inactivation of cAMP signalling pathway
1. EC ligand/receptor binding reversible 2. Deactivation of G protein by hydrolysis of GTP to GDP 3. Phosphodiesterase breaks down cAMP: decrease in [cAMP] in cell 4. Phosphatase removes phosphate on target effector
58
Other 2nd messengers
NO cGMP
59
NO as a 2nd messenger
Gas, free radicals, diffuses across plasma membrane & affects nearby cells Synthesised from arginine & oxygen by NO synthase NO activates guanylyl cyclase which synthesises cGMP – toxic at high concentration
60
cGMP as a 2nd messenger
Synthesised from GTP using guanylyl cyclase in response to NO Triggers cell response by activating cGMP-stimulated kinase or Protein Kinase G (PKG) cGMP induces blood vessel relaxation (smooth muscles) Phosphodiesterase breaks down cGMP
61
2nd messengers involved in the Inositol Phospholipid Pathway
``` Combination of several 2nd messengers: • DAG • PIP • IP3 • Ca2+ ```
62
Inositol Phospholipid Pathway
1. Activation of GPCRs 2. G-protein (G-alpha-q) activates phospholipase C 3. PLC hydrolyses PIP2 to DAG & IP3 4. DAG (hydrophobic) recruits to membrane & activates PKC 5. IP3 (soluble) diffuses through cytosol, binds receptors on ER triggering Ca2+ release into the cytosol 6. Ca2+ binds to effector proteins: – PKC: increases its activation – Calmodulin – cytosolic Ca2+ binding protein
63
Cell response to the Inositol Phospholipid Pathway
Cell division FAST: PKC phosphorylates effector protein SLOW: calmodulin activates CAM-kinase (calmodulin dependent protein kinase) – CAM kinase phosphorylates transcription factors on the chromosome

BGM2002 CS (14 decks)

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