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Advanced Developmental Biology > Lecture 5 - cell-cell interactions: TGF-beta & FGF signalling > Flashcards

Lecture 5 - cell-cell interactions: TGF-beta & FGF signalling Flashcards

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1
Q

Why is interaction important in development?

A

Important interaction allows decision making during development and production of right cells in the right places.

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2
Q

What are the 3 common features of signal transduction pathways?

A
  • Reception
  • Transduction
  • Response
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3
Q

Describe reception

A

The ligand (growth factor, signalling molecule) binds to a cell surface receptor and activates it.

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4
Q

Describe transduction

A

receptor activation initiates a cascade of secondary messenger molecules, which transmit the ‘message’ from the membrane to the nucleus

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5
Q

Describe response

A

A transcription factor is activated and induces the transcription of specific target genes.

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6
Q

What is paracrine signalling?

A

a ligand produced by a cell, navigates locally, through the extracellular space and acts on nearby cells to initiate a response. Usually occurs by binding a receptor at the cell membrane. Cell response occurs through signal transduction - the conversion of signal from one way to another.

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7
Q

What is the TGF-B superfamily (transforming growth factor - beta)?

A
  • consists of 30+ dimeric ligands (2 monomers joined together via disulphide bonds.
  • divide the family into 2 branches
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8
Q

What is the TGF-B Super Family broken into?

A
  • TGF-B-like Family
  • BMP-like Family
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9
Q

What can be found in the TGF-B-like family?

A
  • TGF-Bs: TGF-B1, TGF-B2, TGF-B3
  • Activins: Activin A/AB/B; Inhibin A/B
  • Nodal
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10
Q

What can be found in the BMP-like Family?

A
  • BMPs: BMP1-10, BMP 15
  • GDFs: GDF1-15
  • AMH
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11
Q

What does the TGF-B like family do?

A

plays an important role in formation of extracellular matrix, between cells, surrounds cells, plays a role in the mechanical properties of tissues - e.g. bone ligaments, cell division & formation of tumours.

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12
Q

What do activins & Nodal do?

A

plays an important role in early development - e.g. differentiation of mesoderm, L/R asymmetry (internal organs differ from L/R side.

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13
Q

What does the BMP-like family do?

A

BMP (bone morphogenetic protein) - role in bone formation, embryological development role.

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14
Q

What does canonical mean?

A

standard pathway for type of signal

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15
Q

What does canonical TGF-B signalling involve?

A

Smad-mediated signalling

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16
Q

What Smad molecules are initiated through TGF-B-like family activity?

A

Smad2/3

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17
Q

What Smad molecules are initiated through BMP-like family activity?

A

Smad1/5/8

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18
Q

What Smad molecule is initiated through both TGF-B-like Family & BMP-like Family activity?

A

Smad4 (coSmad)

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19
Q

What are the 3 parts of Smad signalling?

A
  1. Reception
  2. Transduction
  3. Response
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20
Q

What occurs in the reception stage of Smad signalling?

A

Ligand-receptor complex = dimeric ligand + 2 x Type 2 receptors + 2 x Type 1 receptor

TGF-B receptors are serine/threonine kinases

Once assembled, the Type 2 receptors activate the Type 1 receptors by phosphorylation of multiple serines/threonine in Gs domain

Ligand (TGF) binds type 2, which recruits type 1 - process is called complex assembly oligomerization.

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21
Q

What occurs in the transduction stage of Smad signalling?

A

Type 1 receptor activates (phosphorylate) Smad proteins, which act as secondary messengers. Smad 2&3 join with coSmad4 and forms a complex. The whole complex then translocates into nucleus and response occurs.

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22
Q

What occurs in the response stage of Smad signalling?

A

Tissue-specific transcription factors module Smad binding to target genes. Smad act as transcription factors which activate other transcription factors, which act on target genes.

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23
Q

What is a common theme in signal transduction?

A

Components change their subcellular localization leading to activation of the pathway.

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24
Q

How is control of BMP signalling is operated through inhibition?

A
  • LIGAND TRAPS bind to ligands, preventing them from activating their receptors.
  • BMP examples: chordin, noggin, follistatin
  • They ensure BMP signals are only activated at the right time & place
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25
How can genetic engineering be used to alter TGF-signalling?
- genetically engineer DNA that encodes a mutated receptor. - this may include a loss-of-function mutation (e.g. kinase dead) - this may include a gain-of-function mutation The DNA is then expressed in cells or an embryo and interferes with signalling.
26
What is Smad2/3 signalling required for?
It is required for mesoderm formation in the early embryo - mediated by Nodal ligands (in zebrafish/xenopus) - called Squint/cyclops in zebrafish (nodal ligands)
27
What is (Oep)?
one-eyed pinhead = mutant for Cripto
28
How are Oep (one-eyed pinhead) mutants rescued?
Through injected of activated Type 1 receptor mRNA
29
How are Oep mutants rescued by injection of activated Type 1 receptor?
As long as Type 1 receptor is activated, Smad proteins function. This means that Cripto is required for ligand-receptor complex to function properly - it is an essential co-receptor for Nodal signalling, an additional factor that binds the ligand-receptor complex at the cell membrane.
30
Describe Receptor Tyrosine Kinases (RTKs) & the process of FGF signalling
- Large family of cell surface signalling receptor - First identified as playing role in cell proliferation, differentiation, survival, migration - Dysfunction can lead to disease - e.g. cancer - This class of receptor mediates signals from extracellular ligands called 'growth factors' - Lots of the time, the ligands aren't freely diffusible - paracrine signalling locally. - 58 RTK genes identified in the human genome, grouped into 20 subfamilies - Some of the receptors specific for one ligand and vice-versa - Others interact with many ligands and vice versa - Mostly exist as monomers when unbound (except Insulin receptors)
31
What determines the specificity of ligand binding?
Extracellular domains, which vary greatly. Single transmembrane domain. Intracellular are highly conserved and have kinase activity. This means they are able to phosphorylate proteins - tyrosine residues that get phosphate groups added.
32
What occurs at a canonical RTK receptor?
- the receptor is activated through ligand binding. RTK ligands are usually monomers, which will bind to 2 receptors. - usually, ligands come together and dimerise. - dimer will bind 2 receptors simultaneously - DIMERIZATION - 2 receptors come together, bringing the intracellular tyrosine kinase domains together - this causes CROSS-PHOSPHORYLATION of the intracellular domains (phosphorylate each other)
33
What occurs as a result of cross phosphorylation?
- increases activity of kinases - stabilised receptor in activate state (even if ligand dissociates) - phosphorylated tyrosine residues create DOCKING SITES for cytoplasmic proteins.
34
Describe canonical RTK (receptor tyrosine kinase) transduction
Phosphorylation sites are 'sticky' to other proteins - they can bind to phosphorylated sites. This mediates downstream effects. - the docking sites in different receptors are distinct, meaning recruitment of different cytoplasmic proteins, and therefore different responses on receptor involved.
35
What are 3 examples of proteins that bind to RTKs?
- PI 3-kinase (inositol lipid pathway) - GTPase-activating protein (RAS/MAP kinase pathway) - PLC-gamma (inositol lipid pathway)
36
What is the key properties that proteins that bind to RTK (receptor tyrosine kinases) have?
SH2 domains (Src homology 2) domain recognises short phosphopeptide: phosphotyrosine - glutamic acid - glutamic acid - isoleucine
37
What are the 2 distinct states in which Ras has?
Ras functions as a switch with 2 distinct states - active & inactive
38
What is Ras?
Ras is an intracellular switch that exists in either an active or inactive state. Switching between states is regulated by state of receptors.
39
If Ras is bound to GDP, what state is it in?
Inactive
40
If Ras is bound to GTP what state is it in?
active
41
What converts Ras to an active state (GTP bound)?
GEFs - guanine nucleotide exchange factors
42
What converts Ras to an inactive state (GDP bound)?
GAPs - GTPase-activating proteins (GAPs)
43
What occurs when Ras is active?
In its active state, Ras is able to interact with downstream effector protein - Raf - activates Raf's serine/threonine kinase activity
44
Describe an example of how docking leads to signal transduction: the Ras pathway
- Binding of GRB2 and Sos coupled receptor to inactive rase - Sos is a GEF - Sos promotes dissociation of GDP from Ras - GTP binds Ras and then it dissociates from Sos
45
What does GRB2 contain?
SH2 domains, as well as SH3 domains, which allow it to bind Sos. Sos is a GEF. This switches Ras from inactive to active. Ros activates Ras, by promoting dissociation of GDP, insertion of GTP, leading to activated Ras at cell membrane.
46
What are the signal transduction downstream of RTKs?
Activated Ras leads to activation of Raf. This activates Mek, which activates Mapk. MapK will then act to affect the transcription of proteins and transcription factors.
47
Describe the mechanisms used to ensure that Ras has a lasting signal, due to Ras being inactivated quickly by GAP proteins.
Signalling occurs through MapK (Map kinase) signalling. Activation requires phosphorylation at 2 sites - serine & threonine, which are separated by 1 amino acid. Dual phosphorylation is a safety switch, as 2 distinct phosphorylation events means accidental activation is unlikely. The factor that phosphorylates MapK is Mek (Map kinase kinase). It uses ATP as an energy source to provide phosphate. Mek is activated through phosphorylation by Raf (aka. Map kinase kinase kinase). Raf itself is activated by binding of activated Ras.
48
How can MapK affect cell behaviour?
Through directly phosphorylating transcription factors (gene transcription), or by phosphorylating other secondary messengers.
49
How many members are in the family of FGF ligands?
22
50
How many receptors do all FGFs signal through?
4
51
What do FGF ligands occasionally do?
dimerize
52
How many subfamilies of FGFs are there?
3: - Paracrine FGFs (largest) - Intracrine FGFs - Endocrine FGFs
53
What are features of Paracrine FGFs?
monomeric ligands that are secreted by cells and bind to receptors on neighbouring cells
54
What are features of intracrine FGFs?
small group of intracrine FGFs - bind to receptors intracellularly without being secreted.
55
What are features of Endocrine FGFs?
Endocrine FGFs act on a longer range through secretion into the bloodstream. Restricted activity of FGFs is in part determined by their expression pattern - e.g. local expression (e.g. lot of FGF8 in limb formation, mesoderm formation, tailbone and in midbrain-hindbrain boundary specification).
56
Why is the nature of FGFs having RESTRICTED EXPRESSION useful?
Restricted expression helps determine where they act
57
Describe the structure of FGF receptors
- Contains 3 Ig-like domains - D1, D2 and D3. - Acid box - Heparin binding site - Transmembrane domain - Kinase domain (kinase split into 2)
58
Where do FGF ligands bind?
Ligands bind to D2+D3
59
What do FGF receptors contain?
genetic domains - 4 receptors mediate effect of ligands
60
What makes up the extracellular domain in FGF receptors (FGFRs)?
made of 3 immunoglobin domains (D1, D2 & D3)
61
Where is the Acid box found?
Acid box found in between D1 & D2 - plays a role in repressing receptor activity in absence of ligand (preventing inappropriate signalling)
62
Where is the Heparin-binding site found?
Found on D2 - receptor activation requires the formation of a larger complex with molecules called 'heparan sulphate proteoglycans' (HSPGs)
63
What is the responsibility of D2 & D3?
responsible for ligand binding and providing specificity (D3 in particular)
64
What is required for FGFR activation by paracrine FGFs?
heparan sulphate proteoglycans (HSPGs)
65
What are HSPGs important for?
extracellular modifiers of cell-cell singalling
66
Explain how HSPGs can affect FGFR activation
- Each sugar can be modified in many different ways, especially sulphation - Polyanionic (negative change) - Modification could result in a "cide" that creates binding sites for specific proteins (e.g. FGF2) Long chains of sugars (heparan) come off proteins core.
67
What are examples of HSPGs?
Syndecan - membrane-bound transmembrane domains Glypican - membrane-tethered Perlecan - secreted - not attached to cell membrane
68
Describe how FGF affinity for HSPGs can affect localization of FGF activity
Paracrine FGFs have a high affinity for HSPGs --> retained and act locally Endocrine FGFs have a low affinity for HSPGs --> diffuse into blood stream HSPGs are associated with cell surface.
69
What are examples of how FGF signalling may trigger different cell behaviours through distinct pathways?
MapK --> FOS (TF) --> cell proliferation Akt --> FOXO (TF) --> cell survival Calcineurin --> NFAT --> cell motility
70
What are some examples of human diseases that may manifest as a result of mutations in FGFRs?
Apert syndrome Achondroplasia Pfeiffer syndrome Lots of congenital ("congenital" refers to a condition or trait that is present from birth) diseases arise from mutations of FGFRs.
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