Term
| What are the 3 main types of cell to cell communication? |
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Definition
Autocrine: signals self
Paracrine: signals neighbors (a holler away)
Endocrine: signals FAR away (like sending a letter) |
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Term
| Is signal transduction specific? |
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Definition
YES
Only produce response in target cells expressing receptor for signaling molecule. Cells lacking receptor for particular stimulus = “blind” to that stimulus |
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Term
| SET-UP of signal transduction? |
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Definition
Basically: Cells need to communicate, they do it via signal transduction
Signalling cells release signalling molecules
These molecules bind on cells with correct receptors
Reception of these signals leads to an internal events within that cell
Basically: Cells need to communicate, they do it via signal transduction
Signalling cells release signalling molecules
These molecules bind on cells with correct receptors
Reception of these signals leads to an internal events within that cell
Signalling Cells -->release signalling molecules --> Attach to specific receptor on Target Cells --> Something happens |
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Term
| BASICs of signal transduction: |
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Definition
1. Signal is received (RECEPTORS MAY ROLE HERE)
2. Signal is amplified (WHAT IS HERE?)
3. Response is usually a change in protein levels of associations.
NOTE: Specificity is possible at all levels and feedback is possible. |
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Term
| What does signal transduction control? |
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Definition
1. Changes in cell metabolism.
2. Cell Survival
3. Cell growth, proliferation, differentiation.
4. Cell migration
5. Response to environmental stimulus.
The cellular response is made by enzymes and TFs.
Different receptors stimulate different downstream events inside the cell. |
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Term
| Signal molecule is also called what? |
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Definition
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Term
| What is the signal transduction pathway? |
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Definition
Signal molecule (ligand)
Binds to a Receptor
This activates Intracellular signalling proteins
This in turn activates an enzymes which makes Second messengers...
Then you have amplification of signal & activation downstream molecules
Target protein
Response |
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Term
| What are the intracellular signalling proteins? |
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Definition
A. Kinases
B. GTP-bindng proteins |
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Term
| What are the two types of KINASES? |
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Definition
1. tyrosine kinases
2. serine/threonine kinases |
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Term
| What are GTP-bindng proteins? |
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Definition
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Term
| What is the pathway of kinase phosphorylation? |
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Definition
A SIGNAL comes in where the KINASE uses ATP --> ADP to Phosphorylate target protein and this turns "ON" the protein which then sends another signal out.
A Phosphatase inactivates by dephosphorylating! |
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Term
| What is the pathway of GTP-binding proteins? |
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Definition
A SIGNAL comes in where GTP KICKS off GDP and BINDS to a G-Protein to turn it ON!
Then signal goes OUT
GTP Hydrolysis inactivates the G-protein by dephosphorylating it. |
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Term
| What is the role of enzymes in signal transduction pathway? What are these called? |
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Definition
Presence of enzymes in signal pathway greatly amplifies signal.
These are called 2nd messengers |
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Term
| What are the 2 types of receptors? |
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Definition
1. Cell surface receptors
2. Intercellular Receptors |
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Term
| What are the types of cell surface receptors? |
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Definition
G-protein coupled receptors
Receptor tyrosine kinases (RTK)
Serine/theonine kinase receptors
eceptors without kinase activity (linked to separate TK)
Ion channel-linked receptors |
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Term
| What are the 4 types of membrane receptors? And what do each do? |
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Definition
1. Ligand-gated channel- ligand binding opens or closes the channel.
2. Receptor-enzyme (Receptor tyrosine kinases RTK, and Serine/theonine kinase receptors)- Ligand binding to these activates an intracellular enzyme.
3. G-protein coupled receptor- ligand binding to a G-protein coupled receptor open an ion channel or alters enzyme activity.
4. Integrin- Ligand binding to integrin receptors alters the cytoskeleton. |
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Term
| How many membrane spanning domains are there for GPCRs and what are these linked to? |
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Definition
7 membrane spanning domains
Linked to a heterotrimeric G-protein (guanine binding protein)
This has alpha, gamma, and beta parts. |
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Term
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Definition
Ligand binds receptor; G-protein attaches to receptor, if not already attached
Ligand binding changes receptor conformation, results in G protein activation by receptor;
2. GDP on alpha subunit displaced with a GTP, causes…
3 Heterotrimeric G-protein breaks up into alpha and beta-gamma groups, each anchored to membrane, exposing sites to bind to effectors
4. alpha subunit (or beta-gamma) interacts with an effector, modulating its activity, which is to convert ATP to cAMP
(NOTE: cAMP goes on to activate protein kinase A which then phosphorylates other proteins --> cellular response
5. alpha subunit has GTPase activity (can hydrolyse GTP to GDP)
6. Once GDP is present on the alpha, G-protein reassociates as a trimer, and leaves the effector, ending the signal. |
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Term
| What are the two major signalling pathways that use GPCR and G-proteins? |
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Definition
1. Creates cAMP as 2nd messenger
(effector protein= adenyl cyclase)
2. Creates DAG & IP3 as 2nd messengers
(effector protein= phospholpase C; PLC) |
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Term
| How does the cAMP signalling stop? |
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Definition
cAMPphosphodiesterase catalyses cAMP to 5’AMP, ending the response
Caffeine inhibits cAMPphosphodiesterase in Nervous System |
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Term
What are the two types of G-proteins?
(GPCRs : signalling pathway using cAMP) |
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Definition
| the heterotrimeric G-protein subunits can be stimulatory (Gs)or inhibitory (Gi) |
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Term
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Definition
| GTPase activity (can hydrolyse GTP to GDP) |
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Term
| What is the summary of G Protein signalling using cAMP? |
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Definition
Receptor binds G protein activation by GTP
subunit acts on adenlylcyclase (can be stimulatory Gs or inhibitory Gi)
Adenlylcyclase changes ATP to cAMP
cAMP binds regulatory PKA releasing catalytic PKA
Catalytic PKA goes to nucleus and activates TFs (CREB)
CREB binds CRE in DNA transcription |
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Term
GPCRs : signalling pathway using DAG & IP3
what is the G protein called? |
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Definition
| Gq which is activated on ligand binding to GPCR |
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Term
GPCRs : signalling pathway using DAG & IP3
What is the Effector protein called? |
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Definition
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Term
GPCRs : signalling pathway using DAG & IP3
What is broken down to a 2nd messenger hereby PLC? |
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Definition
| membrane inositol phospholipid |
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Term
| Summary of G Protein (DAG/IP3) |
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Definition
-Receptor binds G protein -> Activation
-alpha subunit activates phospholipase C (PLC)
-PLC cleaves inositolphospholipid to DAG and IP3
-DAG: activate PKC -> activate TFs
-PLC: increase intracellular [Ca++] -> activate PKC -> activate TFs |
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Term
| What is caused by defects in GPCR signalling? |
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Definition
Retinitis pigmentosa 4 :
Mutation Rhodopsin (rod pigment)
degeneration of photoreceptor cells
in retina
Loss / diminished night & peripheral vision |
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Term
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Definition
Receptor Tyrosine Kinases
Transmembrane receptors with TK activity |
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Term
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Definition
On the cytosolic side, there is a kinase catalytic site. After ligand binds to both receptors in close proximity, using ATP for both receptors they become bound at that site. The receptor is now activated (by dimerization) and now the signal transduction can go on.
EX: Binding of hormone causes dimerization and then autophosphorylation of tyrosine residues - this is what is called intrinsic kinase activity. |
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Term
| What are the steps of Tyrosine Kinases : Signalling pathway? |
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Definition
Ligand binding
Receptor dimerisation
Tyrosine phosphorylation
Kinase activation
Phosphorylation of effector proteins |
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Term
What is the PI3K (effector protein) signalling pathway
using RTKs? |
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Definition
RTK phosphorylates PI3kinase
Phosphorylation activates PI3kinase activity → activates PKB
PKB phosphorylates proteins→ cell survival (inhibition of apoptosis) |
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Term
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Definition
promotes cell survival via BCL-2.
BCL-2 blocks the normal pathway of apoptosis so cell survives.
REMEMBER:
PI3K (Phosphatidyl-inositol 3-kinase)
Phosphorylates membrane phospholipid
Products Activation PKB/AKT cell proliferation & growth
inhibition apoptosis (survival) |
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Term
Activated Receptor Tyrosine Kinases
reveals docking site for proteins (GRB2) and what happens next? |
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Definition
GRB2 (SH2 part of it) binds the phosphorylated tyrosine on the receptor, and then its SH3 part brings SOS to its substrate (Ras)
Therefore SOS = Guanine Exchange Factor (GEF) |
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Term
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Definition
We know GEFS activate GTPases
Therefore
SOS, which is a GEF, activates Ras, which is a GTPase/G-protein.
(Ras is normally bound to GDP, when SOS binds it the GDP is replaced with GTP and so Ras in then active) |
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Term
| In terms of GRB2, what does RTK activation entail? |
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Definition
| Know RTK activation GRB2 SOS Ras activation of MAPK pathway proliferation |
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Term
| Describe the G-protein cycle: The GTP switch |
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Definition
-Ras-GDP is inactive
-With the help of GEF (Guanine_nucleotide_exchange_factor): is the ON Switch. It takes off the GDP and adds GTP
-Ras-GTP is now Active
- A GAP (GTPase activating protein) will now come in and hydrolyze the Ras-GTP back to Ras-GDP. It is the OFF Switch |
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Term
Signal Transduction : The Modules
What are they? |
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Definition
-Ligand of some sort
-Binds to RTK
-Adaptor (GRB2) binds to the phosphorylated tyrosine
-GEF (SOS) activates GTPase (Ras)
-Effector is the signalling. |
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Term
| What is the pathway that activated Ras follows? What are its effectors? |
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Definition
-Active Ras-GTP recruits Raf to membrane
-Hydrolysis of GTP and Ras-GDP leaves Raf
-Raf becomes active
-Raf binds and phosphorylates MEK
-MEK then phosphorylates and activates MAP Kinase.
-MAP kinase goes on to phosphorylate other things.
Bottomw line is that Ras activation initiates a kinase cascade...Remember: kinasesphosphorylate things |
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Term
| What RTK pathway does the insulin receptor use? |
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Definition
Receptor monomers linked by disulfide bonds
Autophosphorylate their tyrosine residues
Use Grb2, Sos, & Ras mediators & stimulate transcription |
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Term
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Definition
| non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. |
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Term
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Definition
are like RTKs but no TK
CK receptors=JAK/STAT |
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Term
| How do Ion-Channel Linked Receptor proteins work? |
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Definition
Convert chemical signal (NT) into electrical signal
Ligand binding → conformational change → gate opens
Often influx of Ca2+ with channel opening
→also acts as 2nd messenger
usually selective to ions ie: Na+, K+, Ca2+, Cl-
EX: Post-synaptic cell of a neural synapse |
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Term
| What is the pathway for steroid hormone receptor signaling? |
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Definition
Hormones bind to Intracellular nuclear receptors...causing them to change shape and the HSP protein leaves it.
Receptors then able to go into the nucleus and bind to HRE (Hormone
Responsive Element) in DNA sequence
Receptors = transcription factors
Receptors also bind Zn2+ = essential for DNA binding |
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Term
| What is special about steroid hormones? |
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Definition
Lipid soluble ligand
Allows it to pass through membrane
Simple, kinase-free signalling
Molecule goes into nucleus |
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Term
Intracellular receptor activation: in the Nervous System what is the role of
Nitric oxide (NO) gas |
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Definition
Relaxes smooth muscle in blood vessel walls
Acetylcholine binds to receptor and pathway goes on to activated NO synthase (NOS) which release NO.
NO diffuses into smooth muscle cell and
keeps guanylylcyclase on which is converting GTP into lots of cyclic GMP
Cyclic GMP.
This yields smooth muscle relaxation |
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