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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
Why can RTKs link many responses to one input?
Many phosphotyrosine residues can act as docking sites for many different relay proteins in different pathways
26
How is convergence seen in RTKs?
Many different pathways signaled by the same RTK can converge into one cellular response
27
What is an example of RTK activation with ras?
RTK -> Ras -> MAPK3 -> MAPK2 -> MAPK -> proteins that cause changes in protein activity and gene expression
28
What does RTK activation of ras promote (cellularly)?
Survival and proliferation
29
What does PTB stand for?
Phosphotyrosine binding domain
30
What is more common: SH2 domains or PTB domains?
SH2 domains
31
What are some examples of proteins that dock on RTKs?
PI-3 kinase, GAP, PLC-gamma
32
What is associated with RTKs (that increase complexity)?
Scaffolds, modulators, adaptors, integrators, etc.
33
What type of receptor is the insulin receptor?
RTK
34
What is the structure of the insulin receptor?
Disulfide bridges holding alpha chains on extracellular side together, beta chains in cytoplasmic side
35
What does insulin do?
Regulate blood glucose levels by increasing cell glucose uptake
36
How does insulin signal to bring more glucose into the cell?
By causing GLUT4 vesicles to bind to the cell membrane
37
What does GLUT4 do?
Glucose transporter (bring more glucose into the cell)
38
If there is no insulin signlaing, where are the GLUT4 vesicles?
In the cytoplasm (not near membrane)
39
What is the signaling pathway of insulin -> GLUT3 receptors?
IR -> IRS-1 -> PI-3 K -> PDKI -> PKB -> rab proteins on GLUT4 vesicles
40
What causes type II diabetes?
Gradual insensitivity to insulin
41
How does insulin relate to lifespan?
Studies shown people who live longer have higher insulin sensitivity, and decreasing insulin levels
42
What enzyme is phosphorylated by the insulin receptor (in the GLUT4 pathway)?
IRS-1
43
What does IRS-1 do?
Converts PIP2 into PIP3 (phosphorylate)
44
How is PKB actiavted?
Binds to PIP3 and gets phosphorylated by PDKI
45
What does PDKI do?
Phosphorylates PKB to activate it
46
What does PKB do?
Phosphorylates GSK3 to inactivate it, and activates GLUT4 vesicles to move to the membrane
47
What does activate GSK3 do?
Phoshorylates glycogen synthase to inactive it
48
What happens when GSK3 is phosphorylated?
It can no longer inhibit glycogen synthase, thus glycogen synthase becomes active
49
In the glycogen synthase pathway of insulin, what enzymes are activated by phosphorylation?
IRS-1, PKB, PDKI
50
In the glycogen synthase pathway of insulin, what enzymes are inhibited by phosphorylation?
GSK3, and glycogen synthase
51
What are the two effects that insulin does to regulate blood sugar levels?
Promotes uptake of glucose (through GLUT4 channels) and storage of glucose (by activating glycogen synthase)
52
What do rab proteins do?
Help movement of GLUT4 vesicles when activated
53
How does desensitization of the insulin response occur?
Insulin signaling also leads to internalization and recycling of the insulin receptors
54
What does insulin signaling impact (besides glucose levels)?
Cell survival and proliferation
55
How does insulin signaling impact cell survival and proliferation?
Downstream effectors include GRB2 and SOS, which go through the ras pathway to promote cell survival and proliferation
56
What is the insulin / ras pathway?
IRS-1 -> GRB2 -> SOS -> ras -> raf1 -> MEK -> ERK -> transcription factors in nucleus
57
Why can reduced calories lead to a longer lifespan?
Lower levels of insulin, less prone to diabetes, no disregulation of mTOR
58
What does mTOR do?
Nutrient sensing
59
True or false: insulin is thought to interact with mTOR
True: this would explain the relationships between insulin and longevity
60
What does IGF simulate for (cellular response)?
Cell survival
61
What is the IGF cell survival pathway?
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
What are the two domains of a receptor?
The ligand binding domain and the effector domain
63
What can you say about two receptors that have the same ligand binding domain?
They react to the same ligand, but they can have different effects
64
What can you say about two receptors that have the same effector domain?
They produce the same effect, but can react to different ligands
65
How can an input be unlinked to its output?
Genetically create a chimeric receptor, which can combine different ligand binding and effector domains
66
What is the advantage of chimeric receptors?
Can understand what certain domains do and what pathways that interact with
67
How are scaffolds used in the Ras-MAPK pathway?
Tether proteins in a specific orientation to enhance interactions and promote a specific response
68
How does altering the scaffolds / effector proteins change the signaling pathway?
It changes the response
69
How can you study what the different phospho-sites on scaffolds do?
Artificially change scaffold and effector proteins, and see what is changed in the signaling pathway
70
True or false: scaffolds can only bring proteins together
False: they can also undergo conformation changes to activate or inhibit other proteins, or have enzymatic activity
71
How can scaffolds prevent proteins from participating in other pathways?
Through localization and / or enzymatic activity
72
What does Akt do?
Central regulator of many aspects in cell biology
73
What is meant by "redundancy pathways"?
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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