Signal Dysregulation Flashcards
What are protein kinases?
Enzymes that transfer phosphate groups from ATP to proteins or substrates
Switches proteins “on/off”
Outline the process of RTK activation
Ligand Binding
Recepter Dimerisation
Transphosphorylation
Signalling Cascade
What are some RTK dysregulation mechanisms that result in increase RTK activation
Mutations- Deletion of the ectodomain leaves mutated RTK constitutively activated
Overexpression leads to increased chance of ligand-independent dimerisation
Autocrine signalling from tumour cells producing their own GF ligands
What is the most common oncogene in humans?
Ras
How is Ras activated?
RTK Activation
Phosphorylation of GDP-Ras to GTP-Ras
What adaptor proteins link RTKs to Sos/GEF?
Grb2 and Shc
What are the 3 downsteam pathways of Ras?
Raf/MAPK/ERK
PI3K/Akt/PKB
Ral-GEFs
What is the Raf pathway responsible for?
Contact inhibition
Anchorage dependence
Cell shape
What is the most important oncological function of the Akt/PKB (PI3K) pathway?
Anti-apoptosis functions
Other functions:
Stimulation of proliferation
Stimulates cell size growth
Promotes angiogenesis and motility
How is Akt dysregulated?
PTEN reverse PI3K activation
What is the function of the Ral-GEFs pathway?
Anchorage independent growth and activation of Rho family proteins (motility and invasiveness)
How is Ras deavtivated?
GTPase activating proteins(GAPs)
GTPases
Note: in many cancers mutations alter the ability of GAP/GTPases to trn off Ras-GTP
What is dual address?
Proteins that normally reside in cytoplasm but move to the nucleus when activated
How does dysregulation of the JAK-STAT dual pathway lead to oncogenesis?
Mutations can create STAT3 proteins which dimerise spontaneously and act as a nuclear transcription factor.
