cell cycle 5: signalling pathways Flashcards
what do cells do in the absence of growth signals?
enter G0 phase
what are the key components of signalling pathways?
kinases: regulate enzyme activity via protein phosphorylation
phosphatases: remove phosphates
adapter proteins: bring interactive partners together
GTP-binding proteins: regulation
what do signalling cascades allow?
- response to extracellular factors
- signal amplification
- signal integration
- modulation by other pathways
- regulation of divergent responses
what is c-Myc?
transcription factor that stimulates cell cycle gene expression to cause entry to cell cycle
what is the signalling pathway for mitogenic growth factor?
binds to receptor -> activates receptor protein tyrosine kinase -> small Gprotein (Ras) -> kinase cascade -> immediate early genes stimulate expresion of other genes
what is the signalling pathway for peptide growth factor?
growth factors occur as dimers -> bring the 2 receptors close to each toher -> multiple tyrosine phosphorylations occur -> activated tyrosines act as docking points for adapter molecules
what do adaptor proteins do?
tyrosine phosphorylation provides docking sites for adaptor proteins -> allows protein-protein interactions to bring together proteins
eg Grb2 protein with SH3-SH2-SH3 domains (SH3 binds to proline richareas, SH2 binds to phosphorylated tyrosines)
what do GTP-binding proteins do?
act as molecular switches
- when signal arrives, GDP is released and GTP binds to activate
what is the ERK cascade?
chain of proteins in the cell that communicate a signal from a surface receptor to DNA in nucleus Raf -> MEK -> ERK -> protein activation and upregulation of regulatory proteins eg c-Myc
what are cyclins?
proteins transiently expressed at specific points in cycle to activate kinases
- M-cyclins produce M-phase promoting factor -> trigger mitosis
- S-cyclins produce start kinases to trigger DNA replication machinery
what do cyclin-dependent kinases do?
- control cell cycle
- present in proliferating cells throughout cell cycle
- activity regulated by interaction with cyclins & phosphorylation
what do activated CDKs do?
phosphorylate proteins to drive cell cycle progression
how is CDK activated?
- CDK and cyclin bind to form inactive cyclin
- CDK-activating kinase and inhibitory kinase both phosphorylate CDK (donating inhibitory & activating phosphate group)
- phosphatase activates CDK by removing inhibitory phosphate
what cyclins and CDKs are required from G0-G1?
c-Myc stimulates transcription of other genes eg cyclin D -> activates CDK4/6 to stimulate cyclin E synthesis
what cyclins and CDKs are required at the metaphase-anaphase checkpoint?
CDK1/cycB pauses mitosis -> kinetchores fully attach -> cyclin B degraded -> CDK1 inactivated -> mitosis continues
what is MPF?
mitosis promoting factor
- complex of CDK1 & cyclin B
how is MPF activated?
(CDK phosphorylated twice ->) phosphatase Cdc25 removes inhibitory phosphate -> MPF phosphorylates Cdc25 -> Cdc25 activated -> positive feedback loop
what is the retinoblastoma gene?
tumour suppressor gene
what happens during retinoblastoma protein regulation?
when CDKs phosphorylate Rb proteins they become inactivated -> this allows transcription factors to bind and upregulate genes such as cyclin E
what is E2F?
transcription factor that upregulates:
- proto-oncogenes (eg c-Myc)
- cell cycle genes (eg CDK2/4, cyclin A/E)
- DNA synthesis genes (eg DNA polymerase, thymidine kinase, thymidine synthetase)
what are the types of CDK inhibitors?
INK4 family: G1 phase CKIs that inhibit CDK4/6 by displacing cyclin D
CIP/KIP family: inhibit all CDKs by binding to CDK/cyclin complex -> regulate S phase CDKs
what is herceptin?
antibody against HER-2 (human epidermal growth factor) receptor - binds to extracellular domain of gf
what is Grb2?
adapter protein that is always found bound to Sos
what is sos?
set of genes that encode guanine nucleotide exchange factors
- Ras-activating protein
what is Ras?
an oncogene
what does sos do?
act on Ras subfamily of small GTPases
- brought up to membrane -> binds to Ras -> forces it to release GDP -> Ras released from sos -> Ras quickly binds another guanine nucleotide -> since GTP is much more abundant than GDP Ras is usually activated
how can Ras be oncologically activated?
by mutations that increase the amount of active GTP-loaded Ras
