BIOL211 L11

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  • Created by: Katherine
  • Created on: 18-04-17 12:27
What are RTK
Involved in many reponses; insulin receptor, vascular endothelial growth factor receptor, platelet derived growth factor receptor, epidermal growth factor receptor, possess intrinsic tyrosine protein kinase activity.
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Do GPCRs have enzyme activity?
They have no endogenous enzymicactivity.
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How are RTKs different to Receptors linked to tyrosine kinases?
Linked have no intrinsic enymic activity - they have a kinase associated with them.
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What does RTK respond to?
Epidermal growth factor
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What is epidermal growth factor?
A small peptide (53 amino acids), It regulates cell growth and proliferation and differentiation
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What are the key domains of EGF receptors?
EGF binding domain (where it binds the ligand), transmembrane spanning a helix, kinase domain (with intrinsic kinase activity), C terminal tail (rich in tyrosine)
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What is the EGF receptor like when it is not bound?
It is inactive. You have an empty binding site. The Tyrosine kinase exhibits minimal activity
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What change happens to the EGF receptor when it is activated?
Goes from a monomer to a diamer
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What does diamerization do?
It brings about the activation of the kinase activity in the cytosolic domain
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What is the kinase activity in the cytosolic domain?
It is phosphorylation of critical tyrosine residues on the cytosolic domain.
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What does auto-phosphorylation of the tyrosine residues do?
It fully activated tyrosine kinase. Tyrosine kinase phosphorylates additional tyrosine residues in the RTK cytoplasmic domain. Creates binding site for additional signalling proteins
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What does activation of EGF receptor by EGF result in?
The formation of an asymmetric kinase dimer
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What is the process of EGF activation?
Kinase active site blocked by activation lip. Asymmetric kinase dimer removes activation lip from receiver kinase active site. Active kinase phosphorylates tyrosine residues
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What is the MAPK pathway?
Mitogen Activated protein kinase pathway
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What is amplification?
Not about moving a signal from A to B, but making a signal big enough to have a profound response
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What is Ras?
A monomeric G protein (monomeric because it has a single subunit).When
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When is Ras inactive?
When it has GDP bound to it
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In the Map K pathway, what happens when you get binding of the EGF?
You get dimerization, activation of the tyrosine and multiple phosporylations of the kinases (these provide docking site for downstream events),
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In the MAP K Pathway, what is the initial docking protein?
GRB2 (An adapter protein), it binds two different proteins as it has two dites o t.
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What is GRB2?
It is a cytosolic adaptor protein. It is a SH2 domain dontaining protein able to bind to phosphotyrosine residues on other proteins.
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RTK autophosphorylation creates...
The phosphotyrosine residues to which the SH2 domain of the GRB2 binds
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What else does GRB2 contain?
SH3 domain that binds SOS.
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What allows the binding of SH2 domain of the GRB2 to bind to the receptor?
Phosphotyrosine residues on the RTK
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What creates the phosphotyrosine residues to which the SH2 domain on the GRB2 binds?
RTK autophosphorylation
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What does autophosphorylation of RTK do?
Creates a binding site for the SH2 domain containing cytosolic adaptor protein GRB2
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What happens to Ras and Sos in this case?
They remain inactive
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How does GRB2 bind to RTK?
Via its SH2 domain.
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What binds to the SH3 domain on GRB2?
SOS
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What does SOS bind to?
Ras
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How does Ras become active?
It is exchange of GDP to GTP, not phosphorylation.
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G proteins act as molecular switches, what is the role of GEFs in this?
Guanine nucletide exchange factor promotes GDP GTP exchange.
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G proteins act as molecular switches, what is the role of GAPs in this?
GTPase Activating protein, accelerate GTP hydrolysis
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Do GEFs promote switching on or off?
On
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Is SOS a GEF or GAP?
GEF -
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How does SOS work?
It binds to the monomeric G protein and prises the structure apart. This allows the GDP to come out and be replace by GTP
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What happens to the two switches, holding onto the GTP
There is an interaction between them and the GTP, whereas with the GDP, they just sort of cradled it.
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What does active Ras do?
It binds the N terminal regulatory domain of Raf.
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How is Raf activated?
Dephosphorylation of one serine binding Raf to 14-3-3 activates Raf.
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How is the active Raf released?
Hydroylsis of Ras GTP to Ras GDP releases active Raf
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What does Raf do?
It activates MEK (Another tyrosine & serine/threonine kinase)
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What does Mek do once activated?
Phosphorylates another kinase enzyme - MAP kinase (the human example is ERK)
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What is a kinase that is phosphorylating a Map Kinase called?
A MAPKK (mitogen activated protein kinase kinase)
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What is Raf referred to if it is a kinsase that phosphorylaes a kinase which phosphorylates a different kinase?
MAP KKK
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What does the active MAPK then do?
It phosphorylates protein kinase p90
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What is the next stage, after phosphorylation of protein kinase, p90?
Active MAPK and p90 migrate to nucleus and phosphorylates TCF and SRF
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What is TCF?
Ternary complex factor
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WHat is SRF?
Serium response factor
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Phosphorylated SRF and TCF bind to...
SRE (serum response element) in early response genes e.g. c - fos = this allows them to activate gene expression
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Card 2

Front

Do GPCRs have enzyme activity?

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They have no endogenous enzymicactivity.

Card 3

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How are RTKs different to Receptors linked to tyrosine kinases?

Back

Preview of the front of card 3

Card 4

Front

What does RTK respond to?

Back

Preview of the front of card 4

Card 5

Front

What is epidermal growth factor?

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