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Advanced Cell Signalling > Stem Cell Signalling > Flashcards

Stem Cell Signalling Flashcards

1
Q

What is a stem cell?

A

A cell which can differentiate and self renew

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2
Q

What cells are able to differentiate into any cell type in the body?

A

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells

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3
Q

What are the medical applications of ES and iPS cells?

A

Regenerative therapies
Disease remodelling
Remodelling organ toxicities

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4
Q

What are iPS cells?

A

They are embryonic like cells but they can be taken from any tissue (somatic cells)

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5
Q

Example of a regenerative therapy this could be used for?

A

Neurodegenerative disease - make new neurons

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6
Q

Where are ES cells derived from?

A

Blastocytes (pre-implantation embryos)

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7
Q

What does pluripotent mean?

A

All germ layers - ectoderm, mesoderm and endoderm

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8
Q

Why can ES and iPS be maintained indefinitely in vitro?

A

because of their ability to self renew

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9
Q

What type of cell cycle do ES and iPS cells have?

A

Fast cycling due to their constant self-renewal and therefore do not have all the checkpoints found in normal cells

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10
Q

What extracellular signals control stem cell self-renewal and differentiation?

A

GFs
Cytokines
Cell-Matrix and Cell-cell interactions

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11
Q

What signalling pathways control stem cell self-renewal and differentiation?

A

Protein kinases
E3 Ub ligases
Post translational modifications

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12
Q

What cell specific gene expression programmes control stem cell self-renewal and differentiation?

A

Transcription factors
Epigenetic modifiers
Non-coding RNAs

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13
Q

What are the 3 main pathways in Stem cell signal transduction?

A

The LIF pathway
A differentiation switch - ERK1/2 signalling
ERK5 pathway

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14
Q

What does LIF stand for?

A

Leukaemia inhibitory factor pathway

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15
Q

What does the LIF pathway promote?

A

Pluripotency and self renewal

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16
Q

What does ERK1/2 signalling promote?

A

Differentiation, not self renewal

17
Q

What does ERK5 signalling promote?

A

Self renewal

18
Q

What is LIF?

A

A cytokine which activates IL-6 family receptors (LIFR and IL-6R)

19
Q

What were ES cells originally cultured on?

A

MEF ‘feeders’ layer - they secrete LIF

20
Q

How does LIF induce self renewal?

A

LIF bind to LIFR -> dimers of LIFR and gp130 join together through a conformational change -> There is a JAK on LIFR and gp130 which are brought together -> JAKs phosphorylate each other -> JAK on LIFR phosphorylates the gp130 -> provides a tyrosine docking site -> STAT3 recruitment via its SH2 domain -> STAT3 tyrosine phosphorylation -> STAT3 forms a homodimer -> detaches from the receptor and translocates to the nucleus -> binds to DNA and recruits transcriptional activation components -> drive gene expression

21
Q

What activates ERK1/2 signalling in ES cells?

A

Fibroblast growth factor (FGF) 4

22
Q

What does ERK1/2 do in the ES cells?

A

Switches off the stem cell genes and induces expression of lineage specific factors

23
Q

Name a TF which promotes self renewal

A

Nanog

24
Q

Name a TF which promotes differentiation into neurons

A

Sox1

25
Q

How does ERK1/2 activation induce differentiation?

A

The FGF receptor is stimulated -> SOS1 activates Ras -> Ras converted into GTP bound form -> Recruit Raf -> Raf is phosphorylated by other kinases -> Raf phosphorylates and activates MEK1/2 -> MEK1/2 phosphorylate and activate ERK1/2 -> ERK1/2 phosphorylates TFs to shut down stem cell genes, can phosphorylate other transcriptional regulators and epigenetic modifiers to induce chromatin remodelling

26
Q

How is SOS regulated?

A

It is autoinhibited in unstimulated cells

27
Q

What is SOS in a complex with in unstimulated cells?

A

DH
PH
REM:CDC25
GRB2

28
Q

What do DH domains have and what do they bind?

A

Lipid binding domains

Phospholipids in the membrane

29
Q

What do PH domains bind to?

A

Phospholipids in the membrane

30
Q

What does REM:CDC25 contain?

A

The catalytic activity

31
Q

What part of the SOS unstimulated complex is autoinhibited?

A

REM:CDC25

32
Q

What happens to the SOS inhibitory complex when FGFR is activated?

A

GRB2 binds to the phospho-tyrosine binding sites on the receptor
REM:CDC25 associates with the Ras
and the other components associate with the phospholipids in the membrane

33
Q

How do ERK5 induce self renewal?

A

Do not know what stimulates it -> Activation of MEKK2 and 3 through dimerisation and phosphorylation of each other -> Phosphorylation and activation of MEK5 -> Phosphorylation and activation of ERK5 -> ERK5 phosphorylates itself on the C-terminal region -> switches on stem cell gene transcription

Advanced Cell Signalling (12 decks)

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