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Cellular Signalling > Tomlinson - RTKs > Flashcards

Tomlinson - RTKs Flashcards

1
Q

State where VEGF may be located

A

Endothelial cells of capillaries

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2
Q

How fast does phosphorylation occur?

A

Less than a milli second

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3
Q

Tyrosine phosphorylation accounts how what proportion of all phosphorylation occuring?

A

0.1%

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4
Q

Which proportion of kinases are tyrosine kinases?

A

10-15%

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5
Q

How many non receptor tyrosine kinases are there?

A

32

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6
Q

Is there a particular preference for Tyrosine phosphorylation to occur based on amino acid sequence?

A

No, based on conformation/accessibility

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7
Q

State where FGF may be located

A

Fibroblasts and endothelial cells

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8
Q

What is amplification of phosphorylation?

A

The induction of kinase cascades to amplify a response

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10
Q

The EGFR receptor displays negative cooperativity. Explain this.

A

Negative cooperativity is when the addition of one EGR molecule on EGFR reduces affinity for the addition of a second EGR. This is because upon EGR binding there is a conformational change which is unfavourable to add a second EGR. Therefore, one bound is high affinity and two bound is the low affinity conformation.

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11
Q

How many human receptor tyrosine kinases are there?

A

58

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12
Q

State where PDGF may be located

A

Endothelial cells and fibroblasts

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13
Q

State where EGF may be located

A

Epithelial cells

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14
Q

State the names of 5 growth factors

A 
Epidermal growth factor (EGF)
Platelet derived growth factor (PDGF)
Nerve growth factor (NGF) 
Fibroblast growth factor (FGF) 
Vascular endothelial growth factor (VEGF)
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15
Q

Which amino acids are prone to Phosphorylation?

A

Tyrosine, Serine, Threonine

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15
Q

State where NGF may be located

A

Neuronal cells

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16
Q

Describe how the Src protein provided evidence for growth factor signalling

A

Rous Sarcoma Virus is a retrovirus which causes cancer in chicken. It is encoded by Src, which encodes a kinase and is normally involved in regulating cell growth. Mutagenic Src however, has been incorporated into the viral genome and exploited to induce cancer. Hallmarks of v-Src induced transformation include rounded cells and actin rich pod osmosis on their basal cell surface. This correlates to invasiveness and metastasis.

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17
Q

How many amino acids does EGF have and how many disulphide bonds?

A

53 amino acids, 3 disulphides

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18
Q

Describe how the EGF receptor provided evidence for growth factor signalling

A

Sequence analysis found a transmembrane region of EGFR, suggesting a signal transducing role between extra and intracellular faces. There was also a downstream domain of homology with the Src kinase, suggesting EGFR has an intracellular kinase domain and therefore may signal through this.

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19
Q

State three ligands of the EGFR member HER4

A

NRG1
NRG3
NRG4

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20
Q

All RTKs share a common intracellular tyrosine kinase domain. The extracellular domains show greater diversity. Give three examples and state the differences between their extracellular domains

A

EGFR: Possesses two cysteine rich domains

Insulin Receptor: two beta transmembrane domains and two alpha domains. Also cysteine rich

NGFR: Possesses immunoglobulin-like domains

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21
Q

State four abnormal functions of RTKs

A

Cancer
Diabetes
Inflammation
Angiogenesis

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22
Q

What motif does the SH2 domain recognise?

A

pY-x-x-0

where 0 = hydrophobic amino acid

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23
Q

State five normal functions of RTKs

A 
Proliferation
Differentiation
Cell Survival
Cell Motility
Shape
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25
Q

Describe the consequence of transphosphorylation, particularly involving the activation loop

A

Following phosphorylation of the tyrosine domain, there is also phosphorylation of Tyr-416 which is located on an “activation loop”. The phosphotyrosine now exposes the normally blocked ATP binding cleft, thereby activating this region.

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26
Q

State the eight regions of the EGFR receptor structure

A

Extracellular: Domains I, II, III, IV
Intracellular: Transmembrane, Juxtamembrane, Tyrosine Kinase, Regulatory region

27
Q

Give an example of a RTK which dimerises with a ligand using multiple contacts and accessory units

A

Fibroblast Growth Factor Receptor, requiring Heparin binding

28
Q

What are the four variants of the traditional Receptor Dimerisation Model?

A
  • Ligand mediated
  • Ligand mediated with receptor contacts
  • Ligand mediated with multiple receptor contacts and accessory molecules
  • Receptor mediated
29
Q

Describe two simple ways in which RTKs may show dysregulated firing

A

Through acquisition of mutations, the RTK may be constitutively active and fire independently of ligand.

The cell may acquire capability of expressing the agonist growth factor for their own growth factor receptor, thereby causing self activation through autocrine signalling

30
Q

State the four members of the EGFR family

A

ErbB1, HER2, HER3, HER4

31
Q

State the dimerisation conformations of the EGFR members

A

ErbB1: Prototypical
HER2: Extended conformation
HER3: Kinase inactive
HER4: unknown

32
Q

State three ligands of EGFR member ErbB1

A

EGF, TGFalpha, AR

33
Q

State the ligands of EGFR member HER2

A

No known ligands

34
Q

State two ligands of the EGFR member HER3

A

NRG1

NRG2

35
Q

Describe the mechanism of Herceptin treating HER2+ Breast and stomach cancers

A

A monoclonal antibody, involved in sequestering dimerisation of HER2. It also induces cellular toxicity. Herceptin-bound HER2 cells are recognised by Fc receptors on natural killer cells. This causes cross linking of receptors and NK killing. As a consequence, HER2 cells undergo apoptosis

36
Q

How can we know ligand binding itself does not stimulate dimerisation?

A

By removing the extracellular part of RTKs, it has been observed that the intracellular region can still dimerise even at low concentrations. Therefore, the extracellular region must be involved in preventing ligand independent dimerisation -> asymmetric activation

37
Q

Describe the Ras/MAPK pathway

A
  1. “Shc” will associate with pY-716 through the SH2 domain
  2. This will recruit “Grb2” to “Shc”, through an SH2 domain also
  3. This will recruit “SOS” to “Grb” via 2 SH3 domains
  4. “SOS” is a type of RasGEF (guanine nucleotide exchange factor)
  5. “SOS” catalyses activation of inactive GDP-Ras to active GTP-Ras
  6. GTP-Ras induces downstream signalling, I.e.
    - Recruitment of MAPKKKs (A-RAF, B-RAF, RAF1)
    - Recruitment of MAPKKs (MEK1, MEK2)
    - Recruitment of MAPKs (ERK1, ERK2)
    - Recruitment of signal transducers Mnk1, Rsk, Ets, Elk1, SAP
    - Cellular responses: proliferation, cell survival etc.

GTP-Ras can also activate PI3K pathway

38
Q

State the bispecific ligands for ErB1 and HER4

A

HB-EGF, BTC, EPR

39
Q

For the EGFR members, where is the extended dimerisation arm found?

A

Extracellular domain 2

40
Q

When did Herceptin gain FDA approval?

A

2010

41
Q

Which Tyrosine does the Ras/MAPK pathway occur on?

A

Tyrosine 716

42
Q

State three pathways which arise as a result of RTK signalling

A
  • Ras/MAPK Pathway
  • PI3K Pathway
  • PLC gamma 1 Pathway
43
Q

Which Tyrosine does the PLC gamma 1 pathway occur on?

A

Tyrosine 1021

44
Q

Describe the structure of the SH2 domain

A

Central beta pleated sheet, surrounded by two alpha helices

45
Q

How many proteins possess SH2 domains?

A

117 proteins

46
Q

Describe the PI3K Pathway

A

Through phosphorylation of Tyrosine-740, the adaptor protein p85 is recruited to pY via 2 SH2 domains. p85 is one subunit of PIK3, and causes activation of the catalytic PI3K subunit p110. PI3K now active, causes catalysis of PIP2 to PIP3. Downstream effectors of PIP3 include TOR, FOXO and BAD.

The conversion of PIP2 to PIP3 is induced by the Ras/MAPK pathway also

47
Q

Which Tyrosine does the PI3-Kinase pathway occur on?

A

Tyrosine 740

47
Q

Which 2 motifs does the SH3 domain recognise?

A

P-x-x-P

R-x-x-K

48
Q

What 2 motifs does PTB recognise?

A

N-P-x-Y

N-P-x-pY

49
Q

What 2 motifs does PH recognise?

A

PIP3

PIP2

50
Q

What does GEF stand for?

A

Guanine Exchange Factor

51
Q

Describe how the SOS RasGEF converts GDP-Ras to GTP-Ras

A

The alpha helical hairpin of SOS inserts into the GDP pocket of Ras-GDP. This causes reorientation of Alanine59 and ejection of GDP. This facilitates GTP binding, and is often visualised through the Switch I and II domains changing in conformation

52
Q

Give 5 examples of proteins which include SH2 domains

A

Src, Syk, GAP, Nck, PLC-y

53
Q

Write the generic equation for phosphorylation

A

Amino acid + ATP –(kinase)–> Phosphorylated Amino acid + ADP

54
Q

Describe the dual functionality of SH2 domains

A
  1. Intramolecular negative regulation by binding to pY on its own tail and inducing folding
  2. Intermolecular bridging (positive activation) which opens up the tyrosine kinase domain and facilitates Tyrosine 416 phosphorylation
55
Q

What does MAP stand for?

A

Mitogen Activated Protein

56
Q

What is the link between PLCy and PLCb?

A

They are isoforms of each other and both catalyse the reaction of PIP2 to IP3 and DAG. One difference is the gamma isoform is activated by RTKs whereas the beta isoform is activated by GPCRs

57
Q

Give an example of an RTK which ligand-dependently dimerises

A

NGF

58
Q

Describe the PLCy pathway

A

Through phosphorylation of Tyrosine 1021, PLCy is recruited through interaction of pY with an SH2 domain. PLCy catalyses PIP2 into IP3 and DAG. PIP2 however, is not freely accessible in vivo and is produced through an interconversion equilibrium: pi / pip / pip2 / pip3 via PI4, PI5, PI3 kinase

DAG due to its hydrophobicity is embedded into the plasma membrane and signals activation of Protein Kinase C. IP3 however migrates to the ER membrane and binds to Ca channels, causing their opening and migration of intracellular Calcium stores out of ER to the cytoplasm. This causes downstream Calcium mediated signalling, involving formation of Calcium-Calmodulin complexes, activation of Calcineurin, and transcription factors such as NFATC and NFKB.

59
Q

Describe how GAP converts GTP-Ras to GDP-Ras

A

The catalytic Arginine789 finger of GAP inserts into the Ras active site, stabilising Glutamine61 and causing GTP hydrolysis

60
Q

What does GAP stand for?

A

GTPase Activating Protein

Cellular Signalling (5 decks)

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