tyrosine kinase receptors Flashcards
what is a kinase?
an enzyme that catalyses the transfer of a phosphate group from ATP to another molecule
what is a receptor tyrosine kinase?
mediate cell-to-cell communication and controlling a wide range of complex biological functions, including cell growth, motility, differentiation, and metabolism
two types of RTK
- ligand binding to a receptor activates kinase domain of the receptor
- ligand binding to receptor causes change in protein domain and kinase binds to receptor
receptor tyrosine kinases vs receptor associated tyrosine kinases
receptor tyrosine kinase is a domain of the ligand receptor
e.g. (insulin/EGF)
receptor associated tyrosine kinase binds to a receptor upon ligand binding
e.g. (Janus Kinase)
structure of RTK
- extracellular domain = ligand binding site
- transmembrane domain = only one, 1 alpha helix
- intracellular domain = some have kinase domain
- Docking sites = cytosolic tail with tyrosine docking sites
activation of EGF receptor
- EGF binds to extracellular domain
- dimerization occurs: two receptors bind together
- tyrosine docking sites are phosphorylated
- phosphorylated Tyr cause relay proteins to bind and activate which amplify cell response
EGF
epidermal growth factor
what deactivates RTKs
tyrosine phosphatases or degradation
key cellular functions of RTK
- growth
- proliferation
- movement
- survival
- differentiation
speed of RTK response
slow/hours
2 examples of effector functions of RTKs
Ras and PI3-kinase
Ras
g-protein that is a target for RTKs.
is a critical relay in signal transduction
Ras inactive state
when bound to GDP
Ras activated state
when bound to GTP
How is Ras activated?
- signal molecule/ligand binds to RTK
- tyrosine docking sights are phosphorylated
- adaptor protein attaches to phosphorylated Tyr
- Ras-activating protein attaches to adaptor protein
- this protein exchanges GDP for GTP in Ras, which activates it
- onward transmission of signal as Ras binds to effectors
what activates Ras
GEFs exchange GDP for GTP which activates it
what deactivates Ras?
GAPs exchange GTP for GDP which deactivates Ras.
they catalyse GDPs dissociation from Ras
GEFs?
guanine nucleotide exchange factors
GAPs?
GTPase activating/accelerating proteins
simple downstream signalling cascade of Ras (MAPK pathway)
Activate Ras -> activated MAP kinase kinase kinase (RAF)
MAP KKK -> activated MAP kinase kinase (MEK)
MAP KK -> activated MAP kinase (ERK)
finally proteins/transcription regulators are activated
Ras -> RAF -> MEK -> ERK
RAF
MAP kinase kinase kinase
MEK
MAP kinase kinase
ERK
MAP kinase
basic PI3K pathways
- ligand bound to RTK
- PI3K binds to phosphorylated Tyr and is activated
- PI3K phosphorylates inositol phospholipid
- the phosphorylated inositol phospholipid is the 2nd messenger
- PIP acts as a docking site for protein kinase 1 which (along with protein kinase 2) activates AKT
- PIP3 also acts as a docking molecule for AKT
