signal transmission within the cell nela pavlíková [email protected]
TRANSCRIPT
G-PROTEIN COUPLED RECEPTOR
- 7 transmembrane segments
G-protein
heterotrimer, composed of 3 different subunits: subunit ~ 33-55kD
- binding place for GDP / GTP
- intrinsic hydrolytic activity for GTP (it binds GTP = activation → hydrolyzing of GTP to GDP = deactivation)
- in deactivated state - it has bound GDP molecule
- it is associated with Gcomplex subunit ~ 35kD
subunit ~ 15kD
- creates Gcomplex
mammals: 20 different G proteins (each contains unique Gsubunit + one of 5 subunits and one of 12 subunits)
Gi
Gs
Gq
Gs
stimulates adenylyl cyclase → synthesis of cAMP → activation of protein kinase A (PAK) → phosphorylation of nearby substrates
cholera toxin: it keeps Gs permanently activated → ↑cAMP
Gi
after activation it inhibits adenylyl cyclase → ↓cAMP pertussis toxin: Gi subunit unable to release GDP → incapable of
activation → cannot inhibit adenylyl cyclase
cAMP is involved in regulation of many ion channels
Gq
not influenced by cholera toxin nor pertussis toxin phospholipase C → inositol-3-phosphate (IP3) → ↑Ca2+ in cell →
CaMKII
→ diacylglycerol (DAG) → protein kinase C both pathways lead to phosphorylation of nearby proteins
Gt
„transducin“ sensitive to pertussis toxin → incapability to release GDP →
inhibition of signalization
Vision: t1 – black-and -white
t2 – colors
occurrence: retina, some stem cells
effector: phosphodiesterase-6 (PDE6)
→ degradation of cGMP
Go
„other“ effectors not known sensitive to pertussis toxin → incapability to release GDP →
inhibition of signalization
occurrence: neural and endocrine tissues, mitotic spindle early development: effect of serotonin on neuron migration
G12/13
activation of REF („Rho guanine-nucleotide exchange factors“) → activation of Rho proteins
occurrence: ubiquitous
RECEPTOR TYROSINE KINASE
RECEPTOR TYROSINE KINASE
growth factors, cytokines, hormones 17 subfamilies of receptors dimerization of receptors necessary (even tetramers) only one transmembrane segment (N-end extracellular, C-end
intracellular) tyrosine phosphorylation = creation of binding domains for cytosolic
signaling proteins → binding → activation of signaling pathways cytosolic signaling proteins: e.g. Src, phospholipase C, PI3-kinase
domains for binding on phosphorylated tyrosines:
SH2 domain (src), PTB domain (PI3-kinase)
RECEPTOR TYROSINE KINASE
endocytosis of activated receptor: destruction of receptor in lysosome ← binding of ubiquitin molecule on
kinase endocytosed receptor signalization – e.g. NGF
RECEPTOR TYROSINE KINASE
Ras, Rho - monomeric GTPases
- anchored in the inner membrane
- a part of receptor tyrosine kinase signaling pathway
- activation: GEF (guanine nucleotide exchange factor)
- inhibition: GAP (GTPase activating factor)
↓
resistance → cancer
Ras → MAP kinase → signalization into nucleus (→ e.g. cell proliferation)
Rho → connect RTK with cytoskeleton (→ cell shape, motility, adhesion)
RECEPTOR TYROSINE KINASE
RECEPTOR TYROSINE KINASE
PI-3 kinase - Akt
RECEPTORS ASOCIATED WITH TYROSENE KINASE
JAK-STAT
RECEPTOR SERINE/THREONINE KINASE
ligand: e.g. TGF- SmaDs → regulatory protein endocytosis → activation
→ degradation
NUCLEAR RECEPTORS
their ligands can cross the cytoplasmic membrane on their own = transcription factors (in activated form they start transcription of
target genes) nuclear receptors activated by ligand vs. „orphan“ receptors
type I – receptor in cytosol → ligand binding → homodimerization
→ transport into nucleus → binding on „response element“ part of DNA → start of transcription
type II – receptor as heterodimer with RXR (and some corepressors) bound in nucleus on „response element“ → ligand into nucleus→ binds to receptor → dissociation of corepressors → start of transcription
answer on the question from the last seminar:synthesis of thyroid hormones