Cell Membranes and Communication > Morphogens- Ellis > Flashcards

Morphogens- Ellis Flashcards

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1
Q

What is a morphogen

A

A signalling molecule that induces tissue development and patterning due to a concentration gradient

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2
Q

What are the three morphogen transport methods

A

Diffusion, relay and transport via protrusions

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3
Q

What is juxtacrine and practice signalling

A

Juxtacrine: Communication with neighbouring cells

Paracrine: Communication in the local area of a cell

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4
Q

Give examples of juxtacrine and paracrine signalling

A

Juxtacrine: Notch
Paracrine: Wnt, Hedgehog

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5
Q

What is the notch pathway involved in

A

Cell fate specification, lateral inhibition, lineage decisions, establish boundaries, cancer, segmentation in vertebrates and proliferation + growth

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6
Q

What are the ligands of notch?

A

Delta, Serrate/Jagged

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7
Q

How conserved is Notch

A

Highly conserved in metazoans, described in Drosphilla, very ancient pathway

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8
Q

How does Jagged 1 interact with the Notch receptor

A

DSL domain interacts with 11th and 12th EGF-like repeat on Notch

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9
Q

What is the DSL domain

A

Delta, Serrate, Lag-2 domain that bindd EGF-like domains on notch

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10
Q

Describe Notch Cleavage

A

Notch binds delta which exerts pull force exposing ADAM10 cleavage site, ADAM10 cleavage exposes γ-secretase cleavage site in transmembrane domain, 2nd cleavage releases Notch intracellular domain (Nicd) which translocates to the nucleus, Nicd interacts with CSL and mastermind to activate target genes

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11
Q

Describe Notch receptor processing

A
  1. Glycosylation by O-fucosyl transferase- chaperones Notch to cell membrane (within E.R)
  2. Furin like convertase activates pro protein by cleaving receptor, non-covalently binds to itself (within Golgi body)
  3. Glycosylation by Fringe, important for interaction with ligand
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12
Q

Describe Notch receptor recycling?

A

Notch receptors are endocytosed to tune the number of active receptors.

Ubiquitination by E3 ligases causes endocytosis

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13
Q

Describe lateral inhibition

A

Lateral inhibition makes neighbouring cells different to each other. Creates a salt and pepper pattern

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14
Q

Describe the mechanism of lateral inhibition

A

Both cells signal each other
One cell will receive slightly more signal
Feed back compounds this difference

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15
Q

How are Notch signals spread?

A

Contact with neighbours

Cellular protrusions for longer range signalling

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16
Q

Examples of lateral inhibition

A

Neuronal cell fate from stem cell

Bristle spacing in Drosphilla

Proliferation in Drosphilla imaginal wing disks

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17
Q

What are focal adhesions

A

Bind cells to extracellular matrix

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18
Q

Describe the structure of integrins

A

Heterodimer, two transmembrane domains which bind to scaffold proteins to link to cytoskeleton.

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19
Q

How many integrins are there

A

24 types in humans (8 β 18 α)
Drosphilla has only 2β 5α

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20
Q

How do integrins bind

A

Reversibly

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21
Q

Name the three integrin conformational states

A

Inactive (folded), intermediate and active (extended)

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22
Q

Talin function

A

Integrins activation
Binds actin and vinculin

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23
Q

Integrin linked kinase (ILK) function

A

Interacts with integrins
Cannot phosphorylate anything

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24
Q

Focal adhesion kinase (FAK) function

A

True kinase
Interacts with Paxillin
Role in cell adhesion and spreading

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25
Vinculin function
Scaffold protein Binds actin + α-actinin or talin
26
Paxilin function
Scaffold protein Adaptor between other elements
27
α-actinin function
Bundles actin filaments
28
Describe the inside out integrin signalling pathway
GTPases activate RIAM which recruits Talin to the plasma membrane to activate integrin
29
What are some functions of outside in signalling
Cell cycle progression (cells must be bound to ECM to undergo mitosis, even metastatic cancer cells) Cell polarity Proliferation
30
What is ILK
A protein with many interactions that can link many pathways such as Wnt, adhesion, cell polarity, spindle assembly etc
31
What is autocrine signalling
Cells signalling to themselves Determines stem cell niches
32
What are the three main receptor classes
Ion channel coupled receptors G-protein coupled receptors Enzyme coupled receptors
33
How conserved is Wnt signalling
Conserved even in basal organisms like sea anemones
34
How many Wnt genes are there
19 in mammals 7 in Drosphilla
35
How is Wnt modified post-transcriptionally?
Glycosylation Palmitoylated
36
How does palmitoylation affect Wnt function
Increases affinity with receptor Interacts with chaperones for secretion Maintains the monomeric form Essential to interact with membranes
37
What is Wnt signalling involved in
Cell fate determination Proliferation Migration Polarity Adhesion Regeneration Cancer Degeneration Diabetes
38
What is the function of Porc
Palmitoylation of Wnt
39
What is the role of Wntless
Chaperones Wnt to membrane Localises to lipid membranes
40
How is Wnt transported in the extracellular space
On exosomes or lipoprotein particles
41
What is the Wnt receptor
Frizzled
42
Describe the structure of Frizzled
7 membrane pass structure, CRD (cysteine rich domain) on extracellular face binds to Wnt lipid Several intracellular domains which bind PDZ proteins
43
44
Describe Wnt/β catenin signalling
When Wnt binds Frizzled, beta catenin binds TCF/LEF transcription factor to activate genes Without Wnt beta catenin is phosphorylated by the destruction complex leading to ubiquitination by β-TrCP. Ubiquitination targets for degradation by proteome
45
What makes up the destruction compex
Axin- scaffold APC- unknown function Casein kinase 1 and glycogen synthase kinase 3 are serine threonine kinases
46
Describe the Wnt binding pathway for β catenin
Wnt binds Fz and LRP5/6 -> Axin binds LRP, mediated by dishevelled-> CK1 and GSK-3 phosphorylate LRP, Axin and APC NOT β CATENIN -> This removes Axin from repressor complex-> GSK-3 phosphorylates proteins at LRP signalsome instead of cytoplasm -> beta catenin is not degraded and activates transcription of LRP and Fz (+Myc and CD44 etc) creating feedback loop
47
Describe the LRP signalsome
Can be endocytosed, receptor complex internalised and MVBs formed. Separates destruction complex and beta catenin before degredation
48
Name other Fz ligands
NDP and Rspo agonise the Wnt pathway Dickkopf proteins inhibit WIF binds Wnt inhibiting pathway
49
Name the three Wnt pathways
Canonical- Wnt/β-catenin Non-canonical- Wnt/PCP pathway Wnt/Ca ion
50
Name the functions of all three Wnt pathways
Wnt/β-catenin- cell fate specification + proliferation Wnt/PCP- Planar cell polarity Wnt/Ca ion- Cell migration and adhesion
51
Describe the Hedgehog pathway's role in development
Epithelial patterning and wing development in Drosphilla Limb bud, notochord and floor plate patterning in vertebrates Cartilage development Peripheral nerve sheath formation Germ cell development Regeneration in planarians
52
Describe Hedgehogs role in maintenance
Mitogen, survival factor and guidance cue Regulation of pain perceptions and cellular metabolism Homeostasis of adult tissues Maintaining neuronal stem cells Inhibiting autophagy Coupling nutrition and growth
53
Describe Hedgehogs role in disease
Congenital malformations Cancer eg basal cell carcinoma and medulloblastoma
54
Describe the french flag model of morphogen signalling
55
Give proof of the french flag model
Chicken limb bud formation is encoded by hedgehog concentration When hedgehog is added ectopically a mirror imagine foot forms
56
What is hedgehog
Hedgehog acts as a morphogen responsible for the patterning of wings and limb buds. The morphology is determined by location and concentration of hedgehog
57
How conserved is hedgehog
Highly conserved in animal kingdom, present in Cnidaria up to vertebrates Even more ancient than Wnt
58
How is hedgehog synthesised
45 kDa precursor Autoproteolytic cleavage of signal sequence Post translational modifications Palmitate added to to N-terminal Cholesterol added to C-terminal
59
What is the function of N-terminal palmitate in hedgehog
Essential for signalling function and signal uptake
60
What is the function of the C-terminal cholesterol in hedgehog
Essential for signal spreading and multimerisation and PTC and Smo interaction
61
Why is Hedgehog transendocytosed
Necessary for maturation and additional modifications by endosome membrane proteins
62
How is hedgehog transported
Exovesicles- always membrane bound
63
Explain the signal transduction pathway of hedgehog
1.Patched (Ptc) is the receptor 2. Ihog, Boi and Dlp are co-receptors 3. If Hh not present Ptc represses Smoothened (Smo) 4. Smo trafficking to plasma membrane blocked leads to degradation
Cell Membranes and Communication
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