Receptor Tyrosine Kinases Flashcards by Zunaira Ali

What are the types of receptors

Receptor tyrosine kinases (RTKs)

Cytoplasmic protien tyrosine kinases

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What are receptor tyrosine kinases

They are receptors that are directly activated by extracellular signals

They have a ligand binding domain

The kinase activity is in one part of the receptor

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What are cytoplasmic protein kinases

They’re indirectly regulated by the ligand

Ex. JAK2

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What are the types or RTK activation

Ligand mediated activation

Receptor mediated activation

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How does ligand mediated activation work

Give a name of a ligand that does this

The ligand has 2 binding sites for each subunit of the receptor

The receptor pieces come together and dimerize (to get activated)

(Ex. Platelet derived growth factor) PDGF

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How does receptor mediated activation work

Give a name of a ligand that does this

Each chain/peice of the receptor binds one ligand

Then the two peices come together as a dimer

Ex. Epidermal growth factor (EGF)

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Each receptor has a

Kinase domain

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What do the kinase domains on receptors do

Phosphorylates the other kinase domain of the receptor prince to activate it

Or Phosphorylates other area of the receptor to make docking sites for the signalling protiens to bind

This is called trans autophosphorylation

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What is the similar in the structure of all the RTKS

They have a domain on the cytoplasmic side of the cell which is the tyrosine kinase domain

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What is special about the insulin receptor

It’s dimer is held together by disulfide bonds

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What is special about the PDGF receptor

It has immunoglobulin like domains

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What is special about the EGF receptor

It has cysteine rich domains

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What are autophosphorylation site

The receptors have these sites

can regulate the receptors kinase activity

Can serve as binding sites for cytoplasmic signalling molecules

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What is the activation loop of a receptor

The loop in the kinase domain of the receptor

Has tyrosine residues that get phosphorylated by autophosphorylation

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How is the kinase activity of a receptor controlled

By autophosphorylation where the tyrosine residues in the activation loop are phosphorylated

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What happens after the activation loop is phosphorylated

It’s stabilized in a position away from the substrate binding site

This leads to activation of the kinase part of the receptor

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After the kinase domain of a receptor is activation what can it do

It can phosphorylate other tyrosine residues of the receptors kinase domains that are next to it

These phosphorylated region can then act as binding site for the cell signalling protiens

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What are the domains of the protiens that bind to the RTKs called

SH2 domain

SH3 domain

PTB

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What is the SH2 domain

SRC homology domain 2

Domain if orotiens where It interacts with the phosphorylated receptor then itself gets phosphorylated

It binds to the phosphotyrosine domains

ex. STAT molecules have SH2

What is the SH3 domain

Domain of a protons that Binds to hydrophobic proline amino acids of other protiens

What is the PTB binding domain

Phosphotyrosine binding domain

Binds phosphotyrosine same as SH2

What type of protiens come to the RTKS

Adaptor protiens (GRB2 bind to the receptor and brings other protiens to it)

Docking protiens (IRS: insulin receptor substrate)

Transcription factors (STATS)

Signaling enzymes (PLC, lipid kinases, phosphatases, GTPase activation protiens)

What is special about GRB2

Has a sh2 domain (binds to receptor) and a sh3 domain (binds to protiens)

What are accessory protiens

They are protiens that help regulate the activity of small g protiens

What are the three types of accessory protiens

Guanine nucleotide exchange factors (GEFs) GTPase-activating protiens (GAPs) Guanine nucleotide dissociations inhibitors (GDIs)

What are GEFs

They stimulate the dissociations of the gdp on the g protiens and promote binding to GTP The activate the G protein

What are gaps

The stimulate hydrolysis of the GTP on the g protien and decrease the duration of the signal They inactivate the g protien

What are GDIs

The inhibit/stop the release of the bound gdp This keeps the GDP on the g protien and keeps it inactive

What protien does the GRB2 bind to

At its SH3 domain it binds to SOS (the son of seven less)

What is SOS

A GEF for the RAS g protien

What is RAS

A G protien that helps in growth and proliferation of cells

How do the accessory protiens help regular the activity of RAS g protien in the MAPK pathway

GAP: shortens the active time of RAS GEF: stimulates the exchange of GDP to GTP which makes RAS active GDI: inhibits the release of GDP to keep RAS inactive when there’s no need for a signal

What is the whole point of a g protiens

To act as a molecular switch to regulate signal transduction

What is special about the docking protien IRS

Gives versatility It gives extra site of phosphorylation once bound to the RTK of the receptor. The receptor phosphorylates it to give it these extra sites It bind to the receptor via a PTB/SH2 domain

What protiens does the docking protien IRS recruit

Shp2: tyrosine phosphatase PI3K: lipid kinase that phosphorylated inositol rings in the 3rd position

What is an example of a signalling protien that goes to the nucleus after being activated

STATs They have an SH2 domain where they need to bind to the receptor and each other to get tyrosine phosphorylated and activated Only then can they go from cytoplasm into the nucleus and act as transcription factor to bind to dna

How can the signal from STATs be shut off

By protiens with cytokine inducible SH2 domains that can bind to the receptor and block docking of STATS Ex. CIS

What are the names of the signalling enzymes that can bind to the receptor and get activated

Shp2 PI3K Pi-PLC All have SH2 domains

What is the point of the mapk pathway

To signal proliferation of cells

What is the first step in the mapk pathway

A ligand binds to the RTK Phosphotyrosines from autophosphorylation on the receptor are used as docking sites for sh2 containing protiens So GRB2-SOS gets bound to the receptor on the inner surface of the membrane Then SOS which is a GEF activate the small g protien RAS

What happens after RAS gets phosphorylated

A phosphorylation cascade where MAPKKK GETS P from RAS THEN MAPKK THEN MAPK

Once the last kinase (MAPK) is phosphorylated what happens

It activates transcription factors ex. Fos and Jun They then go to the nucleus to transcribe the genes for cyclin D1 which makes the cell cycle go from G1 to S phase In the end cell cycle occurs and more cells are made

How does the Mapk pathway get turned off

MKP-1 eventually gets transcribed by the active Fos or jun MKP-1 is a MAPK phosphatase that dephosphorylates and inactivated MAPK This make Fos and jun inactive

What is convergence

Signals from Unrelated receptors (ex. GPCR AND tyrosine kinase receptors) lead to the activation of a common effector Ex. Ex. GPCRS, RTK, and integrins all bind to diff ligands but they can all lead to a docking site for GRB2

What is divergence

A signal from one receptor can lead to activation a a variety of effectors

What is crosstalk

Includes convergence and divergence where Signals can be passed back and forth between pathways Ex. In a GPCR, PKA from cAMP can block RAS from activating MapKKK and then it can just go into the nucleus and regulate the genes it wants to But then in a RTK, RAS wants to activate mapKKK to make Fos or Jim go in the nucleus and regulate its own gene that it regulates