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4/ CAN > Lecture 4 - Cell Signalling and Cancer > Flashcards

Lecture 4 - Cell Signalling and Cancer Flashcards

1
Q

What is intracellular singalling?

A

a set of linked biochemical events that connect a specific biological stimulus with a specific cellular response

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2
Q

Communication between cells control….

A

cell behaviour

  • survival
  • division
  • differentiation
  • apoptosis
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3
Q

Signal molecules bind to specific receptors.

What are the two main types of receptor?

A

intracellular receptors e.g. steroid receptors

cell-surface receptors e.g. for insulin

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4
Q

Describe briefly the intracellular signal transduction pathway

A
  • extracellular signal molecule
  • receptor protein
  • intracellular signalling proteins
  • target proteins e.g. metabolic enzymes, gene regulatory protein, cytoskeletal protein
  • response
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5
Q

What are the tyrosine kinase receptors?

Describe their structure

A

Enzyme coupled receptors are an important class of cell surface receptor

  • Single pass membrane spanning protein
  • Variety of extracellular domains
  • Cytoplasmic TK domain –> phosphorylates tyrosine residues on target proteins
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6
Q

Give examples of some molecules that act through RTKs

A 
EGF
IGF
NGF
MCSF
FGF
VEGF
Eprhins
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7
Q

Which 2 important pathways are activated by signal molecules interacting with receptor tyrosine kinases?

A

MAP (mitogen activate protein) kinase pathway

PI-3-kinase pathway - phosphatidylinositol

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8
Q

Give the 9 simple steps of the MAP kinase pathway

A 
signal molecule
receptor tyrosine kinase
Grb-2
Ras-GEF
Ras
MAP-kinase-kinase-kinase (Raf)
MAP-kinase-kinase (Mek)
MAP-kinase (Erk)
Cell growth
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9
Q

Phosphorylation and dephosphorylation modifies the activity of many target proteins. How?

A

Protein kinases catalyse the transfer of the terminal phosphate group of ATP to specific Set, Thr, Tyr residues on target proteins.
Protein phosphatases dephosphyrlate proteins

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10
Q

Describe dimerisation and autophophorylation and their functions

A
  • Binding of the singnalling molecule induces receptor dimerisation
  • Enable kinase domains of neighbouring receptors to cross-phosphorylate each other on multiple Tyr residues (autophosphorylation)
  • Phosphorylation of Tyr residues creates high-affinity docking sites for a variety of proteins: Grb-2 (MAP kinase pathway) and PI 3-kinase (PI 3-kinase pathway)
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11
Q

What is Grb-2?

What does it do?

A
  • Adaptor protein with SH2 domain which recognises specific phosphorylated Tyr residues on RTK
  • Grb-2 also contains SH3 domain which binds to a proline rich motif in a protein called Sos
  • Assembly of the receptor-Grb2-Sos complex enables Sos to recruit and activate Ras
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12
Q

What is Ras?

Where is it found?

A
  • small protein with GTPase activity

- contains a covalently attached lipid group that attaches it to the plasma membrane

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13
Q

What is Sos?

What does it do?

A

Sos is a guanine nucleotide exchange factor (GEF) which activates Ras by stimlulating it to exchange GDP for GTP

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14
Q

How is Ras inactivated?

A

GTPase activating proteins (GAP) inactivate Ras by stimulating its intrinsic GTPase activity

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15
Q

one word answer:
What turns Ras on?
What turns Ras off?

A 
on = Sos
off = GAP
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16
Q

What does Ras do?

A

onward transmission of signal along multiple pathways

  • Ras is not a kinase but it activates Raf which is a kinase
  • Raf activates Mek
  • Mek activates Erk
17
Q

What are Raf, Mek and Erk examples of?

A

serine threonine kinases

18
Q

What is the role of Erk?

Where do it act?

A
  • Erk phosphorylates a variety of target proteins including other kinases and gene regulatory proteins in the NUCLEUS.
  • The resulting changes in protein activity and gene expression cause complex changes in cell behaviour including cell growth/proliferation
  • Genes activated include: c-jun, c-fos, c-myc, c-myb, cyclin D = all TF’s
19
Q

In what 4 ways can the signal from the MAP kinase pathway be turned off?

A
  • removal of extracellular signal
  • switching off activated receptor tyrosine kinases by protein tyrosine phosphatases e.g. SHP1 and SHP2
  • Ras GAPs
  • desphosphorylation of target proteins by serine/threonine phosphatases
20
Q

Why is tight regulatory of the MAP kinase pathway essential?

A
  • constitutive activation of a protein in the pathway as a result of gene mutation predisposes to cancer
  • many RTKs, Ras, jun, fos, myc etc are oncogenes
21
Q

Give the 7 steps of the PI-3-kinase pathway

A
  • signal molecule
  • receptor tyrosine kinase
  • PI-3-kinase
  • PI(3,4,5)P3
  • PDK1
  • Akt (PKB) –> cell survival
  • Akt (PKB) –> mTOR –> cell growth
22
Q

How is the PI-3-kinase enyzme activated?

What does it then do?

A

by binding to Try residues on RTK

- catalyses the phosphorylation of PIP2 to generate PIP3

23
Q

What is phosphatidylinositol?

Where is it found?

A
  • a phospholipid found in eukaryotic cell membranes

- it is phosphyralted to form PIP, which is phosphphorylated again to PIP2 which is activated by PI-3-kinase

24
Q

What happens down stream of PIP3?

A

PIP3 acts as a docking site for 2 proteins, PDK1 and Akt.

Upon binding PDK1 phosphorylates and activates Akt,

25
Q

How does Akt induced cell survival?

A 
Active Akt (activated by PDK1) phosphorylates a variety of targets including the protein BAD.
Active BAD results in the release of death inhibitory proteins and the prevention of apoptosis
26
Q

How does Akt induced cell growth and cell survival?

via what kinase?

A

Akt interacts with mTOR (kinase)
mTOR complex 1: stimulates cell growth by promoting ribosome production and protein synthesis, and inhaling protein degradation
mTOR complex 2: stimulates cell survival (and cell growth) by helping to activate Akt

27
Q

In what 4 ways and the PI-3-kinase pathway be switched off?

A
  • removal of extracellular signal
  • switching off activated RTKs by protein tyrosine phosphatases
  • dephoshphorylation of target proteins by serine/threonine phosphatases
  • PTEN, an inositol lipid phosphatase which removes phosphate from PIP3, so that it not longer acts as a docking site for PDK1 and Akt
28
Q

What is stratified (personalised) medicine?

A

a more effective way of treating cancer by grouping people according to the genetic lesion within individuals, and then targeting that lesion or signalling pathway to which it contributes

29
Q

What are the two examples of personalised medicine from this lecture?

A

HER2 and Herceptin

BCR-ABL and Gleevec

30
Q

What family is HER2 a member of?
What is meant by it being an ‘orphan receptor’?
How is HER2 activated?
What happens if HER2 is over expressed?

A
  • epidermal growth factor family (EGFR)
  • it has no ligand
  • activated by heterodimerisation with other EGFR family members
  • over expression leads homodimerisation of HER2 –> constitutive signalling (in the absence of a ligand)
31
Q

How does HER2 status influence breast cancer survival?

A

HER2 positive –> 3 years

HER2 negative –> 6-7 years

32
Q

What is the medical management for HER2 positive patients?

A

Trastuzumab (Herceptin)
- humanised anti-HER antibody that causes HER2 internalisation/degradation or ADCC
-

33
Q

Explain BCR-ABL and chronic myeloid leukaemia

A
  • CML usually associated with the Philadelphia chromosome which forms as a result of a translocation between chromosomes 22 and 9
  • breakage and rejoining occurs at the sites of the BCR and ABL genes, creating a hybrid gene that encodes a hybrid BCR-ABL fusion protein
  • ABL is a a cytoplasmic Tyr kinase that promotes cell survival and cell growth
  • Substitution of the normal N-terminus of ABL with BCR, constituently activates ABL Tyr kinase activity
  • BCR-ABL stimulates inappropriate proliferation of haemopoetic precursor cells, and prevents them from dying from apoptosis
34
Q

What is the medical management for CML?

A

Imatinib (Gleevec)
- synthetic ABL kinase inhibitor that blocks the ATP binding pocket of the Tyrosine kinase domain of BCR-ABL (ABL can no longer phosphorylate proteins)

4/ CAN (39 decks)

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