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Biology of Disease > BOD L13 Growth regulation and signal transduction > Flashcards

BOD L13 Growth regulation and signal transduction Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

What are the six main hallmarks of cancer?

A

Sustaining proliferative signalling

Insensitivity to growth inhibitors

Enabled replicative immortality

Induced angiogenesis

Resisting apoptosis

Invasion and metastasis

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2
Q

What is the model for GF signalling?

A

EGF signalling

Family members ErbB1/2/3/4

HER1/2/3/4

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3
Q

How is EGF signalling subverted in cancers?

A

Mutation causes truncated form of protein. Means signalling is consitituitively on, even in absence of ligand.

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4
Q

EGF receptors are transmembrane. What set of events occurs after binding of ligand?

A

Binding of ligand to extracellular domain results in:

  • confomrational change to receptor
  • activation of cytoplasmic tail, which links to downstream pathways via adaptor proteins.
    This effects cell proliferation.
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5
Q

Name a few signalling proteins that act via RTK’s

A
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6
Q

What are the three routes of dimerisation for TKRs?

Give three examples

A

Ligand induced dimerisation, receptor dimersises upon ligand binding, EGF.

Predimerisation, where receptor is dimer and ligand binding alters conformation. - IGF1

Ligand dimers - dimer ligand which causes receptor dimerisation upon binding. - PDGF

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7
Q

What state must RTK’s be to be active?

What event occurs to activate?

A

Must be dimerised to be active.

Autophosphorylation.

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8
Q

How is the phosphorylated tyrosine recoginsed during RTK signalling?

A

By proteins containing SH (Src homology) domains.

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9
Q

What role do SH domain containing proteins perform during RTK signalling?

A

Serve as adaptor proteins to couple receptors to
Ras (GTPase)

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10
Q

What to binding sites are seen in a SH2 domain?

A

Binding site for phosphotyrosine, binding site for amino acid side chain

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11
Q

What is the result of signalling via RTKs?

A

Cascade of protein serine/threonine phosphorylations.

Results in signal being transmitted from cell surface to nucelus, via Ras

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12
Q

How is Ras subverted in cancer?

What is it also known as?

A

Proto-oncogene.

Gain of function mutations to increase activity.

30% of human tumours have hyperactive Ras mutation.

Also known as p21

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13
Q

How is Ras activated and inactivated?

A

Ras is active when bound to GTP, but inactive when bound to GDP.

As a GTPase, it therefore must have continual supply of GTP to be active.

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14
Q

What two proteins influence activity of Ras?

A

Activating - GEF (guanine nucleotide exchange factors exchanges GDP for GTP.

Inactivating - GAP (GTPase-activating proteins) increases rate of GTP hydrolysis on Ras, more GDP.

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15
Q

Where can Ras be found within the cell?

A

Ras is anchored to the cytoplasmic side of the plasma membrane.

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16
Q

How is Ras activated by a RTK?

A

When RTK is activated, adaptor protein binds (with SH domain) which activates a GEF. This provides GTP for Ras activation.

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17
Q

In EGF signalling, what is the adaptor protein?

What is the GEF?

A

GRB.

SOS.

18
Q

Once Ras is activated during RTK signalling, what system relays this?

A

MAP-kinase cascade.

MAP-K-K-K, MAP-K-K, MAP-K

19
Q

What is the most common TKR up-reg in breast cancer?

A

HER2.

25-50 copies of the gene made, 40-100 fold increase in HER2 on cancer cells.

20
Q

What are the main ligands of HER1/2/3/4

A
21
Q

How does HER2 function?

A

It doesn’t have a ligand, so dimerises with other RTKs

22
Q

How does HER2 impact prognosis of breast cancer?

A

Positive cancers are more aggressive and less sensitive to hormone therapy.

But good as can be targeted by mAb therapy (Herceptin)

23
Q

How does herceptin (trastuzumab) work?

A

Blocks downstream signaling pathways from HER2, as well as flags cancerous cells for ADCC

24
Q

What is the most characterised downstream target of Ras?

A

Raf kinase

25
Q

What isoforms of Raf exist?

A

C-Raf (Raf-1)

A-Raf

B-Raf

26
Q

What is Raf kinase?

A

Family of serine/threonine kinases.

27
Q

Which isoform of Raf is implicated to be mutated in 50% of melanoma tumours?

A

B-RAF, V600E mutation

28
Q

Oncogenic mutations of Ras mean what for its binding?

A

Activating mutations cause Ras to be locked in active state, with GTP bound

29
Q

What are the two main effector pathways of Ras?

A

RAF-MEK-ERK.

PI3K.

30
Q

What is the function of PI3K when activated by Ras?

A

Converts PIP2 into PIP3

31
Q

How is PIK3C involved in cancer?

A

Obtains ‘gain of function’ mutation to become oncogenic and is active even in absence of RAS-GTP

32
Q

How can PI3K be activated in the absence of Ras?

A

Stimulated by RTK directly

33
Q

What is the result of PI3K action?

A

PDK1 activation and phos. of Atk (aka PKB)

PKB is antiapoptotic as it phosphorylates cell death protein Bad

34
Q

What two members of Bcl2 family oppose one another in apoptosis?

A

Bad - pro-apoptosis

Bcl2 - anti-apoptosis

35
Q

In proliferating cells, how is Bad inhibited?

A

Phosphorylated, bound to cytoplasmic component (does not play a role in inducing apoptosis)

36
Q

In non-proliferating cells, how is Bad active?

A

Bad is dephoshphorylated and blocks action of Bcl2

37
Q

How does EGF signalling prevent apoptosis?

A
38
Q

What is the important function Atk (PKB) plays during EGF signalling?

A

Anti-apoptotic by phos. Bad

39
Q

What is the therapeutic target against cancer involved in the PI3K signaling pathway?

A

mTOR - PI3K-like kinase (PIKKs)

40
Q

What is a good way of targeting mTOR?

A

Rapamycin.

41
Q

What are two alternative parters of mTOR?

A

Rictor and Raptor.

Rictor - Activates Akt, drives proliferation.

Raptor - Increases protein synthesis, drives cell growth

42
Q

What happens to cancer cells with hyperactive PI3K when treated with rapamycin?

A

Cells are addicted to Atk/PKB proliferation signal.

Rapamycin blocks mTOR stimulation of Akt/PKB. The cells cannot sustain proliferation without Akt and die by apoptosis.

Biology of Disease (17 decks)

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