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4 CAN > 4 Cell Signalling and Cancer > Flashcards

4 Cell Signalling and Cancer Flashcards

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1
Q

What 2 main cell signalling pathways were explored in this lecture?

A

Mitogen activated protein (MAP) kinase

Phosphatidylinositol (Pl) 3-kinase

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2
Q

What do protein kinases do?

A

catalyse the transfer of terminal phosphate group of ATP to Ser, Thr, or Tyr on proteins

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3
Q

What happens in RTK autophosphorylation?

A

binding of the singalling molecule causes dimerisation

kinase domains of neighbouring recepters cross phosphorylate each other

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4
Q

What is Grb-2?

A

growth factor receptor - bound protein 2

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5
Q

What is the SH2 domain on Grb-2 for?

A

recognises specific phosphorylated Tyr residues on RTKs

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6
Q

What does the SH3 domain on Grb-2 do?

A

binds to a proline rich moif in Sos (protein)

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7
Q

What does the assembly of the receptor - Grb-2 - Sos complex do?

A

enables Sos to recruit and activate Ras

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8
Q

How does Sos activate Ras?

A

stimulating it to exchange GDP for GTP

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9
Q

How is Ras inactivated?

A

GTPase activating proteins (GAPs) stimulate GTPase

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10
Q

How does Ras activate Raf?

A

by conformational change

not phosphorylation

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11
Q

What is the function of Erk?

A

phospharylation of target proteins (kinases) and gene regulatory proteins in the nucleus)

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12
Q

Name 5 genes activated by Erk

A 
C-jun
C-fos
C-myc
C-myb
Cyclin D
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13
Q

Name 4 ways in which the MAP signal can be turned off

A

Removing signal
switching off activated RTK
Ras GAPs
dephosphorylation of target proteins

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14
Q

What might switch off the activated RTKs?

A

protein tyrosine phosphatases like SHP-1 and SHP-2

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15
Q

Give 2 examples of Ras GAPs

A

p120(GAP)

neurofibromin

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16
Q

What might dephospharylate target proteins in the MAP signalling pathway?

A

serine phosphatases

threonine phosphatases

17
Q

Why is tight regulatory control of the MAP signalling pathway so important?

A

permanent ‘on’ switching of a protein in the pathway predisposes to cancer

many RTKs, Ras, jun, fos, myc are oncogenes

18
Q

how is Pl-3 kinase activated?

A

binding to phospharylated Tyr residues on RTks

19
Q

What sort of kinase is Pl-3 kinase?

A

a lipid kinase

20
Q

what does Pl-3 do?

A

catalyses the phospharylation of Pl(4,5)P2 to form Pl(3,4,5)P3

21
Q

What is the function of Pl(3,4,5)P3?

A

acts as a docking station for PDK1 and Akt

22
Q

Whathappens when PDK1 binds to Pl(3,4,5)P3?

A

it phospharylates and activates Akt

23
Q

What are the 2 main proteins that active Akt phosphorylates?

A

BAD

mTOR

24
Q

What does phosphorylated BAD do?

A

causes the release of death inhibitory proteins and prevention of apoptosis

25
Q

What does mTOR complex 1 do?

A

stimulates cell growth by:

  • promoting ribosome production and protein synthesis
  • inhibiting protein degradation
26
Q

What does mTOR complex 2 do?

A

stimulates cell survival (and growth) by helping to activate Akt

27
Q

How can the signal be turned off for Pl 3-kinase pathway?

A

stopping extracellular signal
switching off activated receptor tyrosin kinases
dephosphorylation of target proteins
PTEN

28
Q

What is PTEN?

A

inositol lipid phosphatase which removes a phosphate from Pl(3,4,5)P3

no longer acts as a docking site for PDk1 and Akt

29
Q

What does HER2 overexpression lead to?

A

abnormal homodimerisation of HER2

signalling cell survival and growth in the absence of EGFR1

30
Q

What is Trastuzumab?

A

humanised anti-HER2 antibody targeting the HER2 oncoprotein

31
Q

How might HER2 oncoprotein be targeted?

A

HER2 interenalisation / degradation

antibody-dependent cellular toxicity

32
Q

For which patients is trastuzumab useful?

A

HER2 + patients

33
Q

What is the genetic basis of chronic myeogenous leukaemia?

A

translocation between chromosomes 22 and 9 forming the Philadelphia chromosome

breakage/rejoining occurs at BCR and ABL sites, coding for a hybrid BCR-ABL fusion protein

34
Q

What is ABL?

A

cytoplasmic Tyr kinase promoting cell survival and growth

35
Q

What does substitution of the normal N-terminus of ABL with BCR do?

A

activates ABL Tyr kinase

36
Q

What does BCR-ABL do?

A

stimulates inappropriate proliferation of haemopoietic precursor cells, preventing them from apoptosing

XS WBCs in blood stream?

37
Q

What is BCR in this context?

A

breakpoint cluster region

38
Q

What is Imatinib?

A

synthetic ABl kinase inhibitor, blocker ATP binding pocket of the Tyr kinase domain of BCR-ABL

39
Q

In which cases might Imatinib be less useful?

Why?

A

patients with acute CML (clast crisis)

relapse because of resistance due to secondary mutations in Tyr kinase preventing drug binding

4 CAN (21 decks)

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