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Cells to Organisms - Lectures > Lecture 14. Signalling through Receptor Tyrosine Kinases and MAP kinases > Flashcards

Lecture 14. Signalling through Receptor Tyrosine Kinases and MAP kinases Flashcards

1
Q

What can signal transductions be initiated by ?

A

Receptors that contain protein kinases as part of their structure

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2
Q

What is the structure of the insulin receptor ?

A

A dimer of two identical units - an alpha subunit and a beta subunit linked by a disulfide bond

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3
Q

What does each beta subunit in the insulin receptor contain ?

A

A protein kinase domain

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4
Q

What happens on on binding of insulin to the insulin receptor ?

A
  1. The cytoplasmic domain of the receptor which is a tyrosine kinase becomes auto phosphorylated on tyrosine OH groups resulting in activation of the receptor
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5
Q

What does tyrosine kinases phosphorylate ?

A

Tyrosine residues

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6
Q

What do tyrosine kinases catalyse ?

A

The transfer of a phosphoryl group from ATP to the hydroxyl group of tyrosine

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7
Q

What does binding of insulin to its receptor result in ?

A

A conformational change which allows each beta subunit to phosphorylate 3 key tyrosine residues on the other beta loop

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8
Q

What are the three key tyrosine residues ?

A
  1. 1158
  2. 1162
  3. 1163
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9
Q

What does phosphorylation of the three tyrosine residues in the activation loop of the kinase domain of the insulin receptor ?

A

Cause the loop to swing across the structure

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10
Q

What is the conformation of the loop that swings on binding of insulin to its receptor ?

A

It is catalytically active

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11
Q

Where are glucose transporters stored ?

A

Within cells in membrane vesicles

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12
Q

What happens to vesicles when insulin interacts with its receptor ?

A

Vesicles move to surface and fuse with the plasma membrane

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13
Q

What does the fusion of vesicles to plasma membrane result in ?

A

An increase in the number of glucose transporters in the plasma membrane

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14
Q

What happens when insulin levels drop ?

A

Glucose transporters are removed from the plasma membrane forming small vesicles

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15
Q

How are glucose transporters removed from the membrane ?

A

By endocytosis

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16
Q

What do the smaller vesicles fuse with ?

A

The larger endosome

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17
Q

What do patches of endosomes enriched with glucose transporters become ?

A

They bud off to become small vesicles

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18
Q

How are insulin receptor substrates recruited to the activated insulin receptor ?

A
  1. The IRS attaches by its conserved SH2 domain to the phosphorylated receptor and then it becomes phosphorylated on tyrosine residues
  2. The regulatory domain of the lipid kinase phosphoinositide 3-kinase also contains a SH2 domain an thus binds to tyrosine phosphorylated sites on IRS-1
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19
Q

How is insulin signaling terminated ?

A

Through the action of phosphatases

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20
Q

What are three classes of phosphatases ?

A
  1. Protein tyrosine phosphatases
  2. Lipid phosphatases
  3. Protein serine phosphatases
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21
Q

What is the function of protein tyrosine phosphatases ?

A

Remove phosphoryl groups from insulin receptor

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22
Q

What is the function of lipid phosphatases ?

A

Remove phosphoryl groups from inositol lipids (IP3 to PIP2)

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23
Q

What is the function of protein serine phosphatases ?

A

Remove phosphoryl group from activated protein kinases

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24
Q

How is EGF pathway activated by ?

A

Binding of EGF to its receptor

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25
Q

What is the EGF receptor ?

A

A receptor tyrosine kinase that participates in autophosphorylation

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26
Q

What is the structure of the EGF receptor ?

A

A dimer of identical subunits that exists as monomers until EGF binds

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27
Q

How many molecules does the dimer bind ?

A

Two molecules of ligand

28
Q

What happens in EGF dimerisation ?

A

A dimerisation arm binds to a domain within the same monomer in a cyclic configuration

29
Q

What does EGF binding induce ?

A

A conformational change that allows the dimerisation arm to extend from each receptor molecule

30
Q

What does the extension of the dimerisation arm from each receptor molecule do ?

A

Brings the C-terminal region on one receptor into the active site of the partners kinase tyrosine residues on C-terminal tail to become phosphorylated

31
Q

What does EGF signaling lead to ?

A

The activation of a small G protein called Ras

32
Q

What binds to phosphotyrosines on activated RTK ?

A

GRB2

33
Q

What is GRB2 ?

A

An adaptor protein

34
Q

What does GRB2 bind to ?

A

A sos protein

35
Q

What is a Sos protein ?

A

A guanine nucleotide exchange factor

36
Q

What does Sos promote ?

A

Exchange of GDP-Ras (inactive) to GTP-Ras (active)

37
Q

What does Ras activate ?

A

Downstream signaling pathways

38
Q

What is the structure of Grb-2 ?

A

A central SH2 protein domain surrounded by two SH3 domains

39
Q

What does the Grb-2 SH2 domain bind to ?

A

Phosphotyrosine residues on the activated receptor

40
Q

What does the Grb-2 SH3 domain bind to ?

A

Proline rich regions on other proteins

41
Q

How is the EGF signaling pathway terminated ?

A
  1. Phosphatases remove phosphoryl groups from tyrosine residues on EGF receptor and from serine, threonine and tyrosine residues in the protein kinases that participate in signaling cascade
  2. Ras possesses intrinsic GTPase activity. This is accelerated by GAPs which facilitate GTP hydrolysis
42
Q

What is the signal in mammals and drosphilia ?

A
  1. EGF

2. boss

43
Q

What is the RTK in mammals and drosphilia ?

A
  1. EGF receptor

2. sev

44
Q

What is the adaptor protein in mammals and drosphilia ?

A
  1. Grb-2

2. Drk

45
Q

What is the GDP/GTP exchange factor in mammals and drosphilia ?

A

Sos

46
Q

What is the effector in mammals and drosphilia ?

A

Ras

47
Q

What is the response in mammals and drosphilia ?

A
  1. Cell growth

2. Photoreceptor cell

48
Q

What is cancer characterised by ?

A

Uncontrolled cell growth

49
Q

What is one of the most commonly mutated genes in human cancer ?

A

Ras

50
Q

What does the most common cancer mutation lead to ?

A

Loss of ability of Ras protein to hydrolyse GTP

51
Q

What is their a widespread over occurrence of in cancer ?

A

Protein kinases

52
Q

What is gleevac ?

A

A rationally targeted anti-cancer drug

53
Q

What do 90% of patients with chronic myelogenous leukaemia show ?

A

A specific chromosomal defect (philadelphia chromosome) in affected cells

54
Q

What causes the c-abl gene to be inserted into bcr gene ?

A

Translocation of genetic material between chromosomes 9 and 22

55
Q

What does translocation of genetic material between chromosome 9 and 22 result in ?

A

Fusion protein known as BCR-ABL

56
Q

How does gleevac work ?

A

Tyrosine kinase inhibitor of BCR-ABL

57
Q

What does Her-2 stimulate ?

A

Cell growth

58
Q

How does Her-2 receptor work ?

A

Signal even in absence of ligand it adopts an extended dimerisation arm us thus constitutively acitve

59
Q

Where does amplification of Her-2 gene occur ?

A

Approximately 25% of breast cancer patients

60
Q

What is a treatment of Her-2 protein herceptin ?

A

Development of monoclonal antibodies

61
Q

What are some monoclonal antibody therapies ?

A
  1. Herceptin

2. Cetuximab

62
Q

What does herceptin result in ?

A

Enhanced receptor degradation and recruitment of immune cells resulting in antibody dependent cellular cytotoxity

63
Q

How does cetuximab work ?

A

Targets the EGFR expressed in colorectal cancers. The body inhibits the EGFR by competing with EGF for binding to the receptor.

The antibody also sterically blocks the dimerisation arm preventing extension, blocking signal pathway

64
Q

What is iressa ?

A

A small molecule tyrosine kinase inhibitor

65
Q

What are farnesyl transferase inhibitors ?

A

Inhibit enzymes that farnesylate Ras, which localises it to plasma membrane

66
Q

What is BAY43-906 (sorafenib) ?

A

A kinase inhibitor that targets ATP binding of Raf

Cells to Organisms - Lectures (36 decks)

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