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BIO 317 > 8 - Signaling through Receptor Tyrosine Kinases > Flashcards

8 - Signaling through Receptor Tyrosine Kinases Flashcards

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1
Q

What are the three largest classes of cell-surface receptor proteins?

A

Ion channel linked, G-protein linked, and enzyme linked

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2
Q

How can an RTK be dimerized (two mechanisms)?

A

Either the signaling molecule can be a dimer, or the signaling molecule can bring together two dimers by a conformational change

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3
Q

What does RTK stand for?

A

Receptor tyrosine kinase

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4
Q

How many times do RTKs pass the cell membrane?

A

Once (single pass)

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5
Q

What do protein-tyrosine kinases do?

A

Phosphorylate tyrosine residues on various target proteins (including themselves)

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6
Q

What do protein-tyrosine kinases regulate?

A

Cell growth, division, differentiation, survival, and migration

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7
Q

What are the steps for RTK signaling?

A
  1. Ligand induced dimerization
  2. Autophosphorylation of subunits
  3. Binding of effector proteins
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8
Q

Why do RTKs use autophosphorylation?

A

Phosphorylation in the catalytic domain increases the kinase activity of the RTK

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9
Q

What does phosphorylation inside the catalytic domain of an RTK do?

A

Increases kinase activity

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10
Q

What does phosphorylation outside the catalytic domain of an RTK do?

A

Creates docking sites for other proteins

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11
Q

What domain is needed to dock onto phosphorylated RTKs?

A

SH2 domain

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12
Q

What are the two major divisions of tyrosine kinases?

A

Membrane bound receptors, and cytoplasmic non-receptors

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13
Q

What is the structure of an RTK (from top to bottom)?

A
  1. Ligand binding domain (extracellular)
  2. Transmembrane / juxtamembrane domain
  3. Tyrosine kinase domain
  4. Carboxy-terminal tail
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14
Q

Where are non-receptor tyrosine kianses found?

A

Associated to other receptors (on cytoplasmic side)

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15
Q

What do RTKs have a lot of homology with?

A

Src

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16
Q

What does the tyrosine kinase domain of an RTK do?

A

Autophosphorylation (create docking sites) and transphosphorylation (activate an enzyme)

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17
Q

What activates protein kinase activity in RTKs?

A

Dimerization of receptors

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18
Q

What is cis-autophosphorylation?

A

Subunit phosphorylates itself

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19
Q

What is trans-autophosphorylation?

A

Subunits phosphorylate each other

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20
Q

What are the three ways in which signaling molecules can cross link receptors?

A
  1. Dimer (signaling molecule)
  2. Monomer brought together by proteoglycan
  3. Cluster on membrane (concentration)
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21
Q

What do glycosaminoglycans do?

A

Act similar to extracellular scaffolds to help bind together RTK dimers

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22
Q

How are relay molecules activated by RTKs?

A

Binding to docking sites (phosphotyrosines)

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23
Q

True or false: the order of the tyrosine kinase residues is irrelevant

A

False: specific proteins can bind to specific positions, leading to specificity in the downstream responses

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24
Q

True or false: RTKs generally only link one input to one response

A

False: RTKs can link many responses based on one input

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25
Q

Why can RTKs link many responses to one input?

A

Many phosphotyrosine residues can act as docking sites for many different relay proteins in different pathways

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26
Q

How is convergence seen in RTKs?

A

Many different pathways signaled by the same RTK can converge into one cellular response

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27
Q

What is an example of RTK activation with ras?

A

RTK -> Ras -> MAPK3 -> MAPK2 -> MAPK -> proteins that cause changes in protein activity and gene expression

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28
Q

What does RTK activation of ras promote (cellularly)?

A

Survival and proliferation

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29
Q

What does PTB stand for?

A

Phosphotyrosine binding domain

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30
Q

What is more common: SH2 domains or PTB domains?

A

SH2 domains

31
Q

What are some examples of proteins that dock on RTKs?

A

PI-3 kinase, GAP, PLC-gamma

32
Q

What is associated with RTKs (that increase complexity)?

A

Scaffolds, modulators, adaptors, integrators, etc.

33
Q

What type of receptor is the insulin receptor?

A

RTK

34
Q

What is the structure of the insulin receptor?

A

Disulfide bridges holding alpha chains on extracellular side together, beta chains in cytoplasmic side

35
Q

What does insulin do?

A

Regulate blood glucose levels by increasing cell glucose uptake

36
Q

How does insulin signal to bring more glucose into the cell?

A

By causing GLUT4 vesicles to bind to the cell membrane

37
Q

What does GLUT4 do?

A

Glucose transporter (bring more glucose into the cell)

38
Q

If there is no insulin signlaing, where are the GLUT4 vesicles?

A

In the cytoplasm (not near membrane)

39
Q

What is the signaling pathway of insulin -> GLUT3 receptors?

A

IR -> IRS-1 -> PI-3 K -> PDKI -> PKB -> rab proteins on GLUT4 vesicles

40
Q

What causes type II diabetes?

A

Gradual insensitivity to insulin

41
Q

How does insulin relate to lifespan?

A

Studies shown people who live longer have higher insulin sensitivity, and decreasing insulin levels

42
Q

What enzyme is phosphorylated by the insulin receptor (in the GLUT4 pathway)?

A

IRS-1

43
Q

What does IRS-1 do?

A

Converts PIP2 into PIP3 (phosphorylate)

44
Q

How is PKB actiavted?

A

Binds to PIP3 and gets phosphorylated by PDKI

45
Q

What does PDKI do?

A

Phosphorylates PKB to activate it

46
Q

What does PKB do?

A

Phosphorylates GSK3 to inactivate it, and activates GLUT4 vesicles to move to the membrane

47
Q

What does activate GSK3 do?

A

Phoshorylates glycogen synthase to inactive it

48
Q

What happens when GSK3 is phosphorylated?

A

It can no longer inhibit glycogen synthase, thus glycogen synthase becomes active

49
Q

In the glycogen synthase pathway of insulin, what enzymes are activated by phosphorylation?

A

IRS-1, PKB, PDKI

50
Q

In the glycogen synthase pathway of insulin, what enzymes are inhibited by phosphorylation?

A

GSK3, and glycogen synthase

51
Q

What are the two effects that insulin does to regulate blood sugar levels?

A

Promotes uptake of glucose (through GLUT4 channels) and storage of glucose (by activating glycogen synthase)

52
Q

What do rab proteins do?

A

Help movement of GLUT4 vesicles when activated

53
Q

How does desensitization of the insulin response occur?

A

Insulin signaling also leads to internalization and recycling of the insulin receptors

54
Q

What does insulin signaling impact (besides glucose levels)?

A

Cell survival and proliferation

55
Q

How does insulin signaling impact cell survival and proliferation?

A

Downstream effectors include GRB2 and SOS, which go through the ras pathway to promote cell survival and proliferation

56
Q

What is the insulin / ras pathway?

A

IRS-1 -> GRB2 -> SOS -> ras -> raf1 -> MEK -> ERK -> transcription factors in nucleus

57
Q

Why can reduced calories lead to a longer lifespan?

A

Lower levels of insulin, less prone to diabetes, no disregulation of mTOR

58
Q

What does mTOR do?

A

Nutrient sensing

59
Q

True or false: insulin is thought to interact with mTOR

A

True: this would explain the relationships between insulin and longevity

60
Q

What does IGF simulate for (cellular response)?

A

Cell survival

61
Q

What is the IGF cell survival pathway?

A

RTK -> PI-3 kinase -> PIP3 (from PIP2) -> allows binding of PDK1 and Akt -> Akt is phosphorylated by PDK1 and mTOR -> phosphorylate bad in inhibit it -> prevent inhibition of apoptosis-inhibition protein, thus inhibiting apoptosis

62
Q

What are the two domains of a receptor?

A

The ligand binding domain and the effector domain

63
Q

What can you say about two receptors that have the same ligand binding domain?

A

They react to the same ligand, but they can have different effects

64
Q

What can you say about two receptors that have the same effector domain?

A

They produce the same effect, but can react to different ligands

65
Q

How can an input be unlinked to its output?

A

Genetically create a chimeric receptor, which can combine different ligand binding and effector domains

66
Q

What is the advantage of chimeric receptors?

A

Can understand what certain domains do and what pathways that interact with

67
Q

How are scaffolds used in the Ras-MAPK pathway?

A

Tether proteins in a specific orientation to enhance interactions and promote a specific response

68
Q

How does altering the scaffolds / effector proteins change the signaling pathway?

A

It changes the response

69
Q

How can you study what the different phospho-sites on scaffolds do?

A

Artificially change scaffold and effector proteins, and see what is changed in the signaling pathway

70
Q

True or false: scaffolds can only bring proteins together

A

False: they can also undergo conformation changes to activate or inhibit other proteins, or have enzymatic activity

71
Q

How can scaffolds prevent proteins from participating in other pathways?

A

Through localization and / or enzymatic activity

72
Q

What does Akt do?

A

Central regulator of many aspects in cell biology

73
Q

What is meant by “redundancy pathways”?

A

Cells have different pathways to achieve the same thing (eg. both proliferate and inhibit apoptosis to survive)

BIO 317 (27 decks)

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