Wk 4 Signal Transduction and Metabolic Changes in Cancer Flashcards
How does receptor-mediated signal transduction occur?
- ligand/growth factor binds receptor on cell membrane
- Binding causes modification to intracellular portion of receptor
- -> cascade of events in cytoplasm
- -> amplification (receptor effects 1 protein and many other effected downstream) = cytoplasmic effects
- nuclear effects occur too, like gene expression changes
- can have signal divergence = multiple pathways activated by single receptor
7.
What are 3 consequences of a ligand/growth factor binding to a cellular receptor?
- amplification ->
- cytoplasmic and/or nuclear effects
- signal divergence
How are the signals turned off after ligand binding to receptor?
- negative feedback loops from downstream proteins
- signalling inhibitors (block b/c not ready to activate pathway)
What are the 2 main proteins involved in cell signaling?
- kinases
- GTPases
What are kinases?
proteins that add phosphate groups to other proteins or to themselves
What are 2 main types of kinases?
- tyrosine kinases - take phosphates from ATP and add them to tyrosine
- Serine/threonine kinases - phosphorylate serine or threonine
-phosphorylation often transitions protein to active form
What are phosphatases?
Remove phosphates from proteins
What are 2 examples of tyrosine kinases?
- EGFR = epidermal growth factor receptor
- HER2 = related protein (IMP in breast cancer)
3 examples of serine/threonine kinases
- RAF
- MEK
- AKT
What happens when a protein is phosphorylated?
- enable specific phospho-binding proteins to interact with it (stability, degradation, localization)
- if it’s an enzyme, becomes activated or inactivated
- Changes the protein’s conformation (expose nuclear localization sequence and translocation into nucleus)
What is RAS?
A small GTPase
-comes in 3 forms, H-Ras, K-Ras, and N-Ras
What is GDP and GTP?
GDP = signaling “off” = guanosine diphosphate
GTP = signaling “on” pro-cancer = guanosine triphosphate
What are GDP and GTP?
guanasine diphosphate
guanasine triphosphate
=small proteins that help push GTPases from one state to another
What are GAPS?
GTPase activating proteins - promote hydrolyzation of GTP to GDP, turning GTPases into off state
-ex. p120 Tas-GAP, NF1
-GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event
What are GEFs?
=Guanine exchange factors
-ex SOS
-proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP).
-activate GTPases
What are cancer associations with GTPases?
- K-ras mutations (30% lung cancers, 90% of pancreatic cancers)
- high levels of GEFs, like SOS
- loss of GAPs, like neurofibromatosis 1 (NF1)
What is the RAS/MAPK pathway (growth factor signaling pathway) in cancer?
- EGFR or HER2 receptor is bound by ligand
- binding causes dimerization of the receptor
- -> cross-phosphorylation of the dimer
- phosphorylation causes activation of SOS (a GEF)
- -> Ras activation, promotes GTP-bound form, which
- binds to RAF (a serine/threonine kinase) and activates it
- activates other kinases (MAPK)
- cell proliferates
What other pathway gets activated in addition to the RAS/MAPK pathway?
- EGFR or HER2 receptor bound to ligand
- binding -> dimerization of receptor
- phosphorylation of dimer
- activation of PI3K
- activation of Akt (a kinase)
- PI3K/AKT pathway activated = survival and metabolic alterations
What is the Warburg Effect?
Dr. Warburg discovered in 1931 that cancer cells take up much more glucose than normal cells and convert about 50% of it to lactate through aerobic glycolysis instead of oxidizing it to carbon dioxide even in the presence of oxygen.
Cancer: 50% to lactate, 50% CO2
normal: 10% lactate, 90% CO2
What are the 2 major goals of metabolism for tumor growth?
- proliferating cells (incl cancer) need lots of ATP
- they also need the “biomass” - proteins, nucleic acids, lipids, structural CHO, glucose, and glutamine
What metabolites are needed in significantly greater quantity for proliferating cells?
Glucose and glutamine
What are key steps in cancer metabolism?
- increased growth factor receptors (PI3K pathway)
- increased glucose uptake (more GLUT transporters)
- increased glycolytic pathway enzymes
- shunting of glucose into pentose phosphate pathway to make pentose-ribose-5 phosphate (to build nucleotides w/ addition of glutamine)
- increased glutamine uptake (via c-myc oncoprotein)
- increased protein synthesis
- increased AA uptake (downstream from growth factor signaling)
- export of citrate from TCA cycle to cytosol to allow synthesis of FA
What is PI3K and what is its role?
=phospholipid kinase
-transfers the terminal phosphate from ATP to a phospholipid, PIP2, converting it to PIP3
What does mTOR do?
activates and increases growth-factor dependent metabolic changes:
1. glucose transport
2. glycolytic gene expression
3. glycolytic rate
4. lipogenic gene expression
5. lipid synthesis
6. AA transport
How is cytosolic acetyl-CoA produced?
- citrate enters cytosol from mitochondria
- citrate lyase catalyzes ATP to donate P to citrate, CoA added -> acetyl-CoA formation, and oxaloacetate
- FAS reactions - catalzyes 5 reactions: forms oxidized 4C chain attached to ACP that must be reduced. NADPH reduces twice. This steps is repeated multiple times until 16C palmitate is formed and attached to ACP. ACP cleaved by thioesterase -> saturated FA C16, palmitate.
Reactions catalyzed by FAS
C
