9. Tyrosine kinases Flashcards
what does tyrosine kinase do
role in signal transduction
binds to ligands that eventually induce change in cell be a) altered protein function or b) altered gene expression
2 tyrosine kinase families?
- Receptor Tyrosine Kinases
2. Receptor-Associated Tyrosine Kinases
when tyrosine kinase is part of the cell surface receptor, called
receptor protein tyrosine kinase (RPTK)
when tyrosine kinase is recruited to the cell surface receptor, called
receptor associated tyrosine kinase
examples of RPTKs?
insulin receptor
VEGF
EGF
RPTK structure
3 protein domains:
- globular EC
- transmembrane
- tyrosine kinase
globular EC domain
responsible for ligand binding
transmembrane domain
connects EC domain with the cystolic/tyrosine kinase domain
tyrosine kinase domain
CATALYTIC domain
responsible for cellular signaling
activation of RPTK
- ligand binds to 2 RPTKs, causes dimerization of 2 monomeric units
- dimerization causes activation of the catalytic domain
- which causes intermolecular transautophosphorylation
- phosphorylated cytoplasmic domains will then phosphorylate substrates that are recruited to bind to the phosphorylated tyrosine residues
tyrosine kinase phosphorylation does NOT ______ but, rather ______
induce conformational change
creates binding sites for proteins that are specific to phosphorylated tyrosine residues
all AA sequences that allow binding to recruited substrates need to have?
highly specific AA sequence
phosphotyrosine residue
there is a very low concentration of recruited substances within the cell, and the tyrosine kinase has a very LOW AFF for recruited substrates, so how does this reaction even occur?
via SH2 DOMAIN
what do SH2 domains do?
localize substrates around the tyrosine kinase domain of the receptor
(so, even if low substrate concentration in cytoplasm, rxn can proceed–counteracts high Km)
RATKs
do not have a tyrosine kinase domain attached to them
recruit RAPTKs in order to provide catalytic activity
JAK structure
3 domains
- FERM (responsible for binding to the receptor)
- kinase (responsible for phosphorylating activity)
- SH2
before JAKs can provide tyrosine kinase activity, then need to?
phosphorylate each other
after JAKs phosphorylate each other?
they can phosphorylate the tyrosine residues on the cytoplasmic domain of the receptor itself
then, protein substrates can be recruited to the phosphotryosines
what do JAK and Src kinases have in common?
they can affect many different functions inside the cell, from transcription to protein activity
what are STATs?
Signal Transducers & Activators of Transcription
recruited proteins that attach to the phosphotyrosine residues on the receptor that were phosphorylated by the JAK/Src
do STATs have SH2 domains?
yep
why is JAK/STAT signaling important?
because it allows DIRECT signaling access to the nucleus through STAT dimerization
2 ways tyrosine kinase signaling can be terminated?
- via SOCS
2. via PTP
what are SOCSs and what do they do?
SOCS: suppressors of cytokine signaling
used as a feedback mechanism in order to prevent continuous activation of RAPTKs
SOCS mechanism
JAKs/Srcs activate STATs, causing them to dimerize
STAT dimer travels to the nucleus to begin transcription of several genes
one of these genes codes for the SOCS protein–which can bind to phosphotyrosines from the SH2 domain and prevent any further signaling
what are PTPs and what do they do
Protein Tyrosine Phosphatases
they stop tyrosine kinase signal transduction
mechanism of PTPs?
- dephosphorylating the receptor itself
2. dephosphorylating the recrutied subtrates after being activated
