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Biomolecules & Cells > Mechanisms of Signal Transduction > Flashcards

Mechanisms of Signal Transduction Flashcards

1
Q

5 Types of Signaling

A

Cell Communication (Local vs. Long Range)
Small Molecule Signals (NO)
Contact Dependent (Notch)
Hormonal Signals (Nuclear Receptors)
Peptide Growth Factors (Cell Surface Receptors: Ion Channels, GPCRs, Tyrosine Kinase Receptors)

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2
Q

Tyrosine Kinase Pathways

A

Promote proliferation (random mention)

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3
Q

Modes of Cell Communication between Animal Cells

A

Endocrine
Paracrine
Neuronal
Contact Dependent

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4
Q

Endocrine

A

Long-Range Signaling
Ligand is synthesized in the endocrine cell, enters bloodstream, meets far away receptors in one or many places at the same time.
Can involve cell surface receptors, but often nuclear receptors are involved.

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5
Q

Paracrine

A

Ligand is synthesized in the paracrine cell, travels very locally and meets the receptor on a nearby cell, not necessarily traveling via bloodstream at all.
Also, autocrine is possible, just less common.

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6
Q

Neuronal

A

A synapse is the EXTREME of a paracrine signal, since the synaptic cleft is such a short distance to travel.

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7
Q

Contact-Dependent

A

The membrane-bound ligand on the signaling cell meets a membrane-bound receptor on an ADJACENT (not neighboring) cell.

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8
Q

Notch

A

Think of Notch as a light-switch.
If Notch is on, it drives the cell to differentiate towards one specific fate. If Notch is off, it drives the cell towards a different fate. The fact that it is contact-dependent facilitates the emergence of patterns in the layout of different cell types (crucial to the formation of tissues and structures).

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9
Q

A’s Notch Ligand binds Adjacent B’s Notch Receptor

A

The Ligand is upregulated in A, and the receptor is downregulated. (becomes nerve cell)

The receptor is upregulated in B, and the Ligand is downregulated. (becomes epithelium)

Now all the receptor-presenting cells are of one type, and will interact with their neighbors appropriately.

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10
Q

Acetylcholine elicits different responses in different targets

A

In heart muscles, it decreases rate/force of contractions.
In salivary gland cells, it triggers secretions
In skeletal muscle cells, it induces contraction.

The point is, a ligand’s action depends on which tissues carry the receptors for it (and depends on which sort of receptors they have), and different tissues will respond to the same ligand in different ways.

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11
Q

Often you need multiple factors at once to achieve one task

A

A, B, C tell you to survive
D, E tell you to divide
F, G tell you to differentiate

Without A, B and C, the others are useless because the cell dies.

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12
Q

Overall generic signaling pathway

A 
Ligand binds receptor on cell surface
Intracellular signaling proteins are activated
Target proteins either:
Regulate Genes,
Alter Metabolism,
of Alter Cytoskeleton (Shape/Movement)
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13
Q

Relay Transduction

A

One protein signals to another protein to another to another.

Why?
Crosstalk. Different signaling pathways can interact and affect each other. Having multiple steps allows multiple outcomes when different pathways talk. Also, amplification.

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14
Q

Kinase

A

A kinase is an enzyme that adds a phosphate residue to either Serine, Threonine or Tyrosine.
A kinase can be “on” or “off” meaning actively phosphorylating, or not.

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15
Q

Kinase Cascade (MAPK)

A

Ligand binds receptor, triggers phosphorylation of a kinase. That kinase phosphorylates the next kinase. That one phosphorylates the next. Eventually we phosphorylate a target protein that alters gene transcription.

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16
Q

Cell-Surface Receptors

A

GPCRs
Tyrosine
Serine/Threonine Kinase

OMG look they are polar/hydrophilic

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17
Q

Cytosolic or Nuclear Receptors

A

Most hormones

OMG look they are nonpolar/hydrophobic

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18
Q

NO leads to vasodilation (Pathway)

A

Nerve terminal releases ACh
ACh diffuses past smooth muscle and binds surface receptor on endothelial cell.
Endothelial cell is triggered to produce NO.
NO diffuses rapidly and targets smooth muscle cell
Smooth muscle cell relaxes

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19
Q

Basic questions to ask

A

How is signal transmitted across the membrane?
What is the mechanism of transmitting signal from cytosol to nucleus?
How is transcription activated?

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20
Q

Contact-Dependent Signaling (Angiogenesis)

A

Growth of a blood vessel from a pre-existing blood vessel. (Starting from scratch, or de novo, is called vasculogenesis)

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21
Q

Tip cell

A

Presents Notch Ligand (Delta), and is termed “Notch Off”

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22
Q

Stalk Cell

A

Presents Notch Receptor, and is termed “Notch On”

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23
Q

On/Off represent

A

Whether or not the receptor is expressed.

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24
Q

Steps

A

Delta binds Notch on adjacent cells.
Adam10 or TACE cleaves the extracellular moiety of Notch.
Gamma-Secretase cleaves the intracellular moiety (NICD), which travels to the nucleus and binds to CSL, turning it from a repressor into an activator. This locks in the cell fate of stalk, not tip.

This only works when the cells are docked. Soluble Delta doesn’t do shit.

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25
Q

Sidenote about gamma-secretase

A

Also cleaves beta-amyloid. Alzheimers families may have a mutation in this.

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26
Q

Other applications of Notch

A 
CD8 = Notch On
CD4 = Notch Off

Can be used to promote differentiation, can be used to block differentiation. Depends on the context. Just think of notch as a switch.

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27
Q

Notch 1 & Notch 4 controls

A

Endothelial Cells

28
Q

Notch 3 controls

A

Smooth Muscle cell differentiation (vascular)

29
Q

Notch 1 & Notch 2

A

Neuronal
Epithelial
Immune

30
Q

Notch on (vascular)

A

Artery

31
Q

Notch off (vascular)

A

Vein

32
Q

Notch even more off

A

Lymphatic system

33
Q

Steroid Hormone Receptor Signaling

A

Hydrophobic molecule moves across the membrane
Binds to a receptor either in cytosol or nucleus
Moves to the nucleus
Transcription is regulated through nuclear receptor dimerization. Monomers can’t find the right site. Buddy system.

34
Q

Cell Surface Receptors

A

Many of these ligands have two binding sites, requiring the receptor to dimerize in order to bind the ligand securely.

Altered protein function, cytoplasmic machinery, cell behavior happens FAST (seconds to minutes)

Altered Gene Expression happens SLOWLY (minutes to hours)

35
Q

Ion channels

A

Can be receptors to ligands that control gating.

36
Q

GPCRs

A

7 TM Domains (ALL OF THEM)
Extracellular side interacts with ligand.
Intracellular side interacts with alpha, beta and gamma subunits

37
Q

Enzyme-Linked Receptors

A

Tyrosine Kinase and Serine/Threonine Kinase

Receptors are ENZYMES.

38
Q

Two forms of Kinase Receptors

A

Intrinsic - Receptor itself is a kinase

Extrinsic - Receptor binds ligand, and ASSOCIATED protein is the enzyme.

39
Q

Kinase signaling OR GPCR signaling

A

We must invoke molecular SWITCHES. These allow signal to be rapidly turned on or off.

40
Q

Kinase Cascade Signaling

A

Signal On: Kinase phosphorylates a substrate. Phosphorylated substrate propagates the signal.
Dephosphorylating the substrate turns the cascade/signal “off.”

41
Q

GPCR Signaling

A

G-proteins bind to GDP or GTP.
Off - GDP-bound
On - GTP-bound.

Conformational change based on which is bound, propagates (or doesn’t propagate) signal. Exchange or hydrolysis turn switch on or off.

42
Q

GPCRs
Huge family (thousands of genes code for versions of these)
Here’s what they have in common:

A

7 TM regions
Interacts with proteins also at the membrane.
Hella druggable

43
Q

GPCR Components

A

7 TM Region Receptor
Partner = Trimeric G Protein
Term “G protein” refers to the fact that it binds GTP/GDP.
Trimer has Alpha, Beta and Gamma subunits.
Alpha and Gamma have a phospholipid tether keeping them attached to the intracellular face of the membrane.

44
Q

GPCR - Inactive

A

GDP is bound to alpha subunit of G Protein Trimer

All 3 trimeric subunits stay togethsies.

45
Q

GPCR - Active

A

Ligand binds receptor.
Receptor undergoes a conformational change on the intracellular side, inducing a conformational change in Alpha.
GDP is ejected. GTP binds instead.
This releases Beta/Gamma from Alpha. This is referred to as the “activated complex”
One signal has become two different active molecules that can do different things.
In the case of Adenylyl Cyclase, ALPHA activates that enzyme to trigger the creation of cAMP from ATP.
Switch turns off almost immediately. This activation is pulsatile.
To turn off, hydrolysis of the GTP by the alpha subunit returns us to the inactive state, and the trimer reassembles.

46
Q

What does Beta/Gamma do?!

A

In heart cells, when Beta/Gamma is released by the switch turning ON, it interacts with previously-closed potassium channels to open them!!!!

47
Q

Second Messenger

A

Small diffusible intracellular products that can diffuse messages quickly and widely throughout the whole cell when activated to act on multiple target proteins.

48
Q

Cyclic AMP

A

[] Rises rapidly in a neuron in response to serotonin

49
Q

What can cAPMP do?

A

One example is activating Protein Kinase A.

50
Q

PKA

A

It is a serine/threonine kinase. It travels to the nucleus and phosphorylates serines & threonines on a transcription factor, causing a change in gene transcription.

51
Q

Another target of Alpha besides Adenylyl Cyclase

A

Phospholipase C

52
Q

Phospholipase C

A

Cleaves Inositol Phospholipid into Diacylglycerol and IP3.
Diacylglycerol (membrane-tethered) activates PKC, a serine/threonine kinase.
IP3 activates intracellular calcium channels, releasing calcium into the cytosol from the endoplasmic reticulum, which ends up interacting with the newly-activated PKC.

53
Q

Other contexts from GPCRs

A 
Fertilized Eggs
Light receptors (light is the ligand)
54
Q

Example - Light Receptor

A 
Rhodopsin molecule absorbs a photon
500 G-proteins are activated
500 Cyclic GMP phosphodiesterase molecules are activated
10^5 cGMP molecules are hydrolyzed
250 Na+ channels close
10^6 to 10^7 Na+ ions per second are prevented from entering for a period of ~ 1s
Membrane potential is altered by 1 mV
Signal is relayed to the brain.
55
Q

Kinase Receptor Signaling

A

Activation = Receptor dimerization because the ligand has two binding sites, OR the ligand is a dimer.
Then there is a lot of activity at the intracellular face of the receptor that starts kinase activity.
Can be in the enzyme of the receptor, itself, or in associated proteins (adaptors/scaffolds).
Ultimately ends in phosphorylation of transcription factors and alteration of gene transcription.

56
Q

Adaptor

A

1 protein that binds

57
Q

Scaffold

A

A large protein that can assemble lots of proteins on it.

58
Q

Intrinsic Receptor TK

A

Enzymatic domain recognizes subset of tyrosines on other proteins and phosphorylates them.
Inactive as a monomer. Very slight enzymatic activity as a monomer.
When a ligand helps dimerize it, The dimer halves phosphorylate each other, activating each other!!!!!!
This recruits hella other signaling molecules to the intracellular face. They bind to the newly-phosphorylated tyrosines. Conformational change. They go off and alter protein activity or gene expression.

59
Q

Examples of TK signals (Proliferation)

A

Recruited adaptor protein bound to newly-activated TK binds Ras-activating protein, which takes Ras-GDP and exchanges the GDP for GTP, activating Ras.
Activated Ras phosphorylates MapKKK, which phosphorylates MapKK, which phosphorylates MapK. MapK phosphorylates proteins to change their actiity, and phosphorylates gene regulatory proteins to alter gene transcription.

60
Q

What happens when we thwart this pathway?

A

CANCER
Mutant Ras can’t hydrolyze GTP, so it stays active, and keeps sending proliferation signals. Switch never turns off.

One of the holy grails for treating cancer has been targeting Ras, but that shit is harddddddd. It’s in so many places, and you can’t parse that shet.

61
Q

Tyrosine Kinase Receptors - Split Receptor (JAK/STAT)

A

Non-cell intrinsic.
Divide the work between the receptor and the TK (two different proteins)
TK = JAK - It’s bound to the receptor, but not the receptor itself.
Dimerization
JAKs phosphorylate each other
Activated JAKs phosphorylate receptor
STATs are recruited to the phosphorylated sites of the receptor.
This facilitates their dimerization.
STAT dimers travel to the nucleus and regulate gene transcription.
In different contexts, different STATs will be used, and different responses occur.

62
Q

Where do you commonly find JAK/STAT TKRs?

A

Immune system!! Often the ligand is a cytokine (which are legion in the immune system)

63
Q

Serine/Threonine Kinase Receptors and their difference from Tyrosine Kinase Receptors.

A

First difference: Doesn’t phosphorylate tyrosines. Phosphorylates Serines and Threonines.
Ubiquitous in all organisms, while TK is pretty limited to multicellular organisms.
Much smaller family than TK

64
Q

TGF-Beta Receptor family (Ser/Thr Kinase)

A

HETEROdimers (Type 1 and Type 2)
One of them phosphorylates the other, and adaptors assemble on that one.
Instead of STATs, we have SMADS.
SMAD binds to activated receptor subunit, gets phosphorylated itself.
Phosphorylated SMAD dissociates and binds a different SMAD, migrating to the nucleus as a pair.
The pair work with other regulatory proteins to alter gene expression.

65
Q

Cross-Talk among signaling pathways

A

G-Proteins can activate Phospholipase C.
Wait, TKs can too!
We can coordinate complicated signaling by combining different pathways.
Sometimes the end targets are the same, or they interact.
Funsies!

66
Q

Methods of crosstalk

A

You can both phosphorylate the same molecule through different mechanisms, and the twice-phosphorylated molecule behaves in a unique way.

You can phosphorylate two separate molecules that fit together in the phosphorylated form.

67
Q

Survival Signaling

A

Involves AKT
Dimerized TK
Adaptor Protein
Recruited enzyme

Biomolecules & Cells (2 decks)

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