Lecture 15 - Signal Processing Pathways II Flashcards
Effector proteins can be
Metabolic enzymes
Gene regulatory proteins
Cytoskeletal proteins
mTOR signalling pathway
Mammalian Target of Rapamycin
pathway inhibited by rapamycin
Rapamycin causes a
Decrease in cellular growth
Eventually causes apoptosis
mTOR is a
Cytoplasmic Kinase
Phosphorylates Ser/Thr residues
mTOR is central to
Control of cellular growth and proliferation
Linked to cancer cell growth
mTOR is regulated by
Growth factors, RTKs, Insulin, Nutrients (a.a. and glucose), cellular energy levels, stress
mTOR complexes into
mTORC1 and mTORC2
The mTOR cascade is activated by
RHEB
Ras Homolog Enriched in Brain
RHEB is
A Ras family small GTPase
When RHEB is bound to GTP it
Activates mTOR (then cells can grow)
The mTOR pathway is regulated by
TSC1 and TSC2
TSCs
Tuberous Sclerosis Complex
TSC1 and TSC2
Inhibit the mTOR pathway (growth suppressors)
TSC2 inactivates
RHEB by GTP hydrolysis - TSC2 is a GAP (GTPase activating protein)
Activated AKT (kinase) phosphorylates and inhibits
TSC2
AKT/PKB
A serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration
Starvation results in
Autophagy
Aktivation of mTOR results in
Phosphorylation of downstream targets
mTORC1
Promotes protein synthesis
Promotes ribosome production
Inhibits protein degradation
mTORC2
Changes actin cytoskeleton and cell shape
mTOR activates S6 kinase that
Phosphorylates ribosomal protein S6
Increases translation of ribosomal components
elF4E
Translation initiation factor
Indirectly activated by mTOR by inhibiting an inhibitor of elF4E
mTOR is a central
Modulator of proliferative signal transduction
Integrates external and internal signals
Co ordinates cellular growth and replication
mTOR is an ideal therapeutic target against
Cancer
Multiple components of pathways that signal through mTOR as dysregulated in cancer
Clinical inhibitors of mTOR
Rapamycin (bacterial toxin)
Immunosuppressants
Anti cancer drugs
Tuberous Sclerosis
Multi system genetic disease
Mutations in TSC1 or 2 (hamartin and tuberin)
Cause non malignant tumours in the brain and other vital organs
Loss of control of cell growth and division
developmental delay, skin abnormalities, lung and kidney disease
Mating factors cause
Polarisation of yeast cells
“Schmooing”
Polarisation of yeast cells
“Schmooing” Steps
- Mating factor - activates G protein
- Activates Cdc42 (Rho family)
- Rho - formin - actin cable formation
- Polarised exocytosis and schmooing
Cdc 42 also activates WASP and ARP complex to
Local actin nucleation at the site of mating factor binding, actin filament polymerisation, actin cable formation (tip growth)
The insulin signalling pathway is a
RTK
Present on the surface of insulin responsive cells (Muscle, Liver, Fat)
RTK have
2 subunits held together by disulfide bonds alpha units (extracellular) bind insulin beta units (transmembrane and intracellular)
Binding of insulin to the RTK causes
Intracellular domains to come together, allowing cross phsophorylation
Leads to docking and phosphorylation of other proteins
Insulin in liver cells results in
Increased glycogen synthesis
A.a metabolism
Growth
Glucose translation
Insulin in muscle cells results in
Increased growth
Myoblast fusion
Glucose translocation
Insulin in fat cells results in
Adipogenesis
Glucose translocation
In less differentiated cells prolonged glucose activation
Leads to long term activation of gene loci - results in cellular differentiation
