Field lecture.pdf
Field lecture.pdf
Field lecture.pdf
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PI-3-Kinase Signaling in Normal and Cancer Cells!<br />
Seth <strong>Field</strong>, M.D., Ph.D.!
PI-3-Kinase Signaling in Normal and Cancer Cells!<br />
• Membranes and lipids!<br />
• Phosphoinositides, Kinases and Phosphatases!<br />
• Growth Factor Signaling Pathways!<br />
• Pathways Downstream of PI-3-Kinase!<br />
• ! Oncogenes/Tumor Suppressor Genes!<br />
• New cancer therapies!
Cell membrane!<br />
• Separate In from Out!<br />
• Pass nutrients!<br />
• Pass waste/toxins/cell products!<br />
• Pass information!<br />
• Provide a surface for 2-D reactions!
Membrane-spanning Proteins!<br />
• Form channels/<br />
pores for passage<br />
of nutrients!<br />
• Receptors carry<br />
information!<br />
• Enzymatic reaction<br />
centers!<br />
A sea of inert lipids!
Glycerol!
Glycerol!<br />
Triglyceride!<br />
= tri-acyl-glycerol!<br />
Fatty acid!
Glycerol!<br />
H!<br />
Diglyceride!<br />
= diacylglycerol!
Diglyceride!<br />
O!<br />
O!<br />
Diacylglycerol!<br />
O!<br />
OH<br />
O!
Diglyceride!<br />
O!<br />
O!<br />
Phosphatidic Acid!<br />
O!<br />
PO4<br />
O!<br />
• ~1 mol% of membrane lipid!<br />
• Exclusively inner leaflet!
Diglyceride!<br />
Phosphatidylethanolamine!<br />
O!<br />
O!<br />
O!<br />
PO4<br />
O!<br />
• ~27 mol% of membrane lipid!<br />
• Inner leaflet > Outer leaflet!<br />
NH3+
Diglyceride!<br />
O!<br />
O!<br />
Phosphatidylcholine!<br />
O!<br />
PO4<br />
O!<br />
• ~29 mol% of membrane lipid!<br />
• Outer leaflet > inner leaflet!<br />
N+
Diglyceride!<br />
Phosphatidylethanolamine!<br />
O!<br />
O!<br />
O!<br />
PO4<br />
O!<br />
• ~27 mol% of membrane lipid!<br />
• Inner leaflet > Outer leaflet!<br />
NH3+
Diglyceride!<br />
O!<br />
O!<br />
Phosphatidylserine!<br />
O!<br />
PO4<br />
O!<br />
• ~15 mol% of membrane lipid!<br />
• Exclusively inner leaflet!<br />
NH3+<br />
O<br />
O-
Inositol!<br />
Diglyceride!<br />
O!<br />
Phosphatidylinositol!<br />
O!<br />
HO<br />
3<br />
HO<br />
O!<br />
OH<br />
4<br />
5<br />
PO4<br />
O!<br />
• ~0.6 mol% of membrane lipid!<br />
• Exclusively inner leaflet!<br />
OH<br />
OH
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
O!<br />
HO<br />
3<br />
HO<br />
O!<br />
OH<br />
4<br />
5<br />
PO4<br />
O!<br />
OH<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI!
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
PO4<br />
O!<br />
HO<br />
3<br />
O!<br />
OH<br />
4<br />
5<br />
PO4<br />
O!<br />
OH<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI!<br />
PI(3)P!
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
O!<br />
HO<br />
3<br />
HO<br />
O!<br />
PO4<br />
4<br />
5<br />
PO4<br />
O!<br />
OH<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI!<br />
PI(3)P!<br />
PI(4)P!
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
O!<br />
HO<br />
3<br />
HO<br />
O!<br />
OH<br />
4<br />
5<br />
PO4<br />
O!<br />
PO4<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI!<br />
PI(3)P!<br />
PI(4)P!<br />
PI(5)P!
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
PO4<br />
O!<br />
HO<br />
3<br />
O!<br />
PO4<br />
4<br />
5<br />
PO4<br />
O!<br />
OH<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI!<br />
PI(3)P!<br />
PI(4)P!<br />
PI(5)P!<br />
PI(3,4)P2!
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
PO4<br />
O!<br />
HO<br />
3<br />
O!<br />
OH<br />
4<br />
5<br />
PO4<br />
O!<br />
PO4<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI!<br />
PI(3)P!<br />
PI(4)P!<br />
PI(5)P!<br />
PI(3,4)P2!<br />
PI(3,5)P2!
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
O!<br />
HO<br />
HO<br />
3<br />
O!<br />
PO4<br />
4<br />
5<br />
PO4<br />
O!<br />
PO4<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI!<br />
PI(3)P!<br />
PI(4)P!<br />
PI(5)P!<br />
PI(3,4)P2!<br />
PI(3,5)P2!<br />
PI(4,5)P2!
Phosphoinositides!<br />
A family of phosphorylated lipids!<br />
Inositol!<br />
Diglyceride!<br />
O!<br />
PO4<br />
PO4<br />
3<br />
4<br />
5<br />
PO4<br />
PI!<br />
O!<br />
HO<br />
O!<br />
PO4<br />
O!<br />
OH<br />
PI = phosphatidyl inositol!<br />
PI(3)P!<br />
PI(4)P!<br />
PI(5)P!<br />
PI(3,4)P2!<br />
PI(3,5)P2!<br />
PI(4,5)P2!<br />
PI(3,4,5)P3 = PIP3!<br />
All are found naturally in cell<br />
membranes of all higher<br />
eukaryotes!
Diglyceride!<br />
Phosphoinositides: A Special Class of Signals!<br />
Obligatorily membrane bound!<br />
O!<br />
O!<br />
PI!<br />
HO<br />
3<br />
HO<br />
O!<br />
OH<br />
4<br />
5<br />
PO4<br />
O!<br />
PI-3-kinase !<br />
(class III)!<br />
OH<br />
OH<br />
O!<br />
PO4 4 OH<br />
3 5<br />
O!<br />
HO<br />
PI(3)P!<br />
O!<br />
OH<br />
PO4<br />
O!<br />
OH
Phosphoinositides: A Special Class of Signals!<br />
Rapidly inter-converted by kinases and phosphatases!<br />
O!<br />
PI(4,5)P2!<br />
HO<br />
3<br />
HO<br />
PO4<br />
4<br />
5<br />
PO4<br />
PO4<br />
OH<br />
PI-3-kinase (class I)!<br />
PI(3,4,5)P3!<br />
PO4<br />
O! O!<br />
O!<br />
O!<br />
O!<br />
O!<br />
PTEN!<br />
(PI-3-phosphatase)!<br />
HO<br />
3<br />
PO4<br />
4<br />
5<br />
PO4<br />
O!<br />
PO4<br />
OH
PI!<br />
PI4K!<br />
Sac1!<br />
Metabolism of Phosphoinositides!<br />
PI(5)P!<br />
PI(4)P!<br />
PI(3)P!<br />
PIPK (II)!<br />
PI3K (II)!<br />
PIKfyve!<br />
Fig4!<br />
PI(4,5)P2!<br />
PI(3,4)P2! PI(3,4,5)P3!<br />
PI(3,5)P2!<br />
PTEN!<br />
PI3K (I)!<br />
SHIP!
PI!<br />
PI4K!<br />
Sac1!<br />
Metabolism of Phosphoinositides!<br />
PI(5)P!<br />
PI(4)P!<br />
PI(3)P!<br />
PIPK (II)!<br />
PI3K (II)!<br />
PIKfyve!<br />
Fig4!<br />
PI(4,5)P2!<br />
PI(3,4)P2! PI(3,4,5)P3!<br />
PI(3,5)P2!<br />
PTEN!<br />
PI3K (I)!<br />
SHIP!
PIP3 Levels on Any Given Membrane Will Reflect the<br />
Balance of Activity of PI3K, PTEN, and SHIP!<br />
And Any Influx/Outflow From Vesicle Trafficking!<br />
PI(4,5)P2!<br />
PTEN!<br />
PI3K (I)!<br />
PI(3,4)P2! PI(3,4,5)P3!<br />
SHIP!
Membrane Phosphoinositide Code!<br />
trans!<br />
Golgi!<br />
cis!<br />
PI4P<br />
PM<br />
PI45P2<br />
ER<br />
nucleus<br />
PI3P<br />
Early !<br />
Endosome!<br />
PI35P2<br />
Lysosome!
Cell membrane!<br />
• Separate In from Out!<br />
• Pass nutrients!<br />
• Pass waste/toxins/cell products!<br />
• Pass information!<br />
• Provide a surface for 2-D reactions!
Cells Need to Monitor and React to Their Environment!<br />
Transmembrane Receptor Complexes Signal Catalytically!<br />
Hormones!<br />
Growth Factors!<br />
Neurotransmitters!<br />
Chemokines!<br />
- Transduction to Second Messengers!
O!<br />
Phosphoinositides: Critical Signal Transducers!<br />
PI(4,5)P2!<br />
HO<br />
3<br />
HO<br />
PO4<br />
4<br />
5<br />
PO4<br />
Levels of PI(3,4,5)P3 Are Tightly Regulated!<br />
PO4<br />
OH<br />
PI-3-kinase (class I)!<br />
PI(3,4,5)P3!<br />
PO4<br />
O! O!<br />
O!<br />
O!<br />
O!<br />
O!<br />
PTEN !<br />
(PI-3-phosphatase)!<br />
HO<br />
3<br />
PO4<br />
4<br />
5<br />
PO4<br />
O!<br />
PO4<br />
OH<br />
• Very low in resting<br />
cells!<br />
• Many signals lead to<br />
elevation of PI(3,4,5)P3<br />
by activating type I<br />
PI-3-kinase!
O!<br />
Phosphoinositides: Critical Signal Transducers!<br />
PI(4,5)P2!<br />
HO<br />
3<br />
HO<br />
PO4<br />
4<br />
5<br />
PO4<br />
Levels of PI(3,4,5)P3 Are Tightly Regulated!<br />
PO4<br />
OH<br />
PI-3-kinase (class I)!<br />
PI(3,4,5)P3!<br />
PO4<br />
O! O!<br />
O!<br />
O!<br />
O!<br />
O!<br />
PTEN!<br />
(PI-3-phosphatase)!<br />
HO<br />
3<br />
PO4<br />
4<br />
5<br />
PO4<br />
O!<br />
PO4<br />
OH<br />
• Very low in resting<br />
cells!<br />
• Many signals lead to<br />
elevation of PI(3,4,5)P3<br />
by activating type I<br />
PI-3-kinase!
PI(3,4,5)P3: Response to PDGF!<br />
BTK-PH-EGFP!<br />
• NIH3T3 Fibroblast!<br />
• Transfect BTK-PH-EGFP (to detect PI(3,4,5)<br />
P3) and dsRed (to mark cell volume)!<br />
• Image Green/Red Ratio (concentration of PI<br />
(3,4,5)P3)!<br />
• Serum starve 50ng/ml PDGF!<br />
30 seconds/frame! <strong>Field</strong> lab data!
Class I PI-3-Kinase is a Heterodimer!<br />
Regulatory!<br />
p110!<br />
PI-3-kinase!<br />
(Class I)!<br />
Catalytic!
Class IA PI-3-Kinase is Activated by RTKs!<br />
Regulatory!<br />
p85!<br />
p110!<br />
PI-3-kinase!<br />
(Class IA)!<br />
Catalytic!
Class IA PI-3-Kinase is Activated by RTKs!<br />
Regulatory!<br />
Two SH2 Domains!<br />
Each can bind a<br />
phosphorylated<br />
tyrosine residue!<br />
p85!<br />
p110!<br />
PI-3-kinase!<br />
(Class IA)!<br />
p85!<br />
Catalytic!
Class IA PI-3-Kinase is Activated by RTKs!<br />
Regulatory!<br />
Two SH2 Domains!<br />
Each can bind a<br />
phosphorylated<br />
tyrosine residue!<br />
p85!<br />
p110!<br />
PI-3-kinase!<br />
(Class IA)!<br />
p85!<br />
Catalytic!<br />
-P!<br />
-Y-X-X-M-!
Class IA PI-3-Kinase is Activated by RTKs!<br />
Regulatory!<br />
Two SH2 Domains!<br />
Each can bind a<br />
phosphorylated<br />
tyrosine residue!<br />
p85!<br />
Ras!<br />
p110!<br />
PI-3-kinase!<br />
(Class IA)!<br />
p85!<br />
Catalytic!<br />
-P!<br />
-Y-X-X-M-!
Class IB PI-3-Kinase is activated mainly by<br />
GPCRs (but also RTKs and chemokine-R)!<br />
Regulatory!<br />
p101!<br />
or!<br />
p87!<br />
p110!<br />
PI-3-kinase!<br />
(Class IB)!<br />
Catalytic!
Class IB PI-3-Kinase is activated mainly by<br />
GPCRs (but also RTKs and chemokine-R)!<br />
Regulatory!<br />
p101!<br />
or!<br />
p87!<br />
Ras!<br />
p110!<br />
PI-3-kinase!<br />
(Class IB)!<br />
Activated by Gβ-γ!<br />
p101/87!<br />
Catalytic!
Class I PI3K Is A Dimer: A Regulatory & Catalytic Subunit!<br />
Class IA - RTK!<br />
regulatory<br />
p85<br />
α<br />
β<br />
γ<br />
p85α<br />
p55α<br />
p50α<br />
p85β<br />
p55γ<br />
(Genes Run in Families)!<br />
SH3<br />
SH3<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
P<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
P<br />
Tissue<br />
distribution<br />
All<br />
Most<br />
Most<br />
All<br />
Brain
Class I PI3K Is A Dimer: A Regulatory & Catalytic Subunit!<br />
Class IA - RTK!<br />
regulatory<br />
p85<br />
catalytic!<br />
p110!<br />
α<br />
β<br />
γ<br />
p85α<br />
p55α<br />
p50α<br />
p85β<br />
p55γ<br />
p110α<br />
p110β<br />
p110δ<br />
85 binding<br />
85 binding<br />
85 binding<br />
(Genes Run in Families)!<br />
SH3<br />
SH3<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
P<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
P<br />
Tissue<br />
distribution<br />
All<br />
Most<br />
Most<br />
All<br />
Brain<br />
All<br />
All<br />
Lymphocytes
Class I PI3K Is A Dimer: A Regulatory & Catalytic Subunit!<br />
Class IA - RTK!<br />
regulatory<br />
p85<br />
catalytic!<br />
p110!<br />
p85α<br />
p55α<br />
p50α<br />
p85β<br />
p55γ<br />
p110α<br />
p110β<br />
p110δ<br />
Class IB - GPCR!<br />
regulatory p87<br />
regulatory p101<br />
catalytic!<br />
p110!<br />
α<br />
β<br />
γ<br />
p110γ<br />
85 binding<br />
85 binding<br />
85 binding<br />
p87<br />
p101<br />
(Genes Run in Families)!<br />
SH3<br />
SH3<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
P<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
P<br />
Tissue<br />
distribution<br />
All<br />
Most<br />
Most<br />
All<br />
Brain<br />
All<br />
All<br />
Lymphocytes<br />
Most<br />
Most<br />
Most<br />
p110β 85 binding Ras binding C2 PIK homology Catalytic domain All
IGF-1 Stimulates Production of PI(3,4,5)P3!<br />
IGF-1<br />
Receptor!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1!Y! -P!<br />
Ras!<br />
PI(4,5)P2!<br />
p85! p110!<br />
PI-3-kinase!<br />
PI(3,4,5)P3!
IGF-1 Stimulates Production of PI(3,4,5)P3!<br />
IGF-1<br />
Receptor!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1!Y! -P!<br />
Ras! PI(4,5)P2! PI(3,4,5)P3!<br />
PTEN! PI(4,5)P2!<br />
p85! p110!<br />
PI-3-kinase!
Phosphoinositides Exert Their Effects via<br />
Specific Binding Proteins!<br />
PI(3,4,5)P3<br />
Binding Protein!<br />
O!<br />
PO4<br />
O!<br />
HO<br />
3<br />
O!<br />
PO4<br />
4<br />
5<br />
PO4<br />
O!<br />
PO4<br />
OH<br />
• They constitute the direct<br />
downstream targets of<br />
phosphoinositides!<br />
• These proteins bind via specific<br />
phosphoinositide binding domains!<br />
• FYVE!<br />
• PH (pleckstrin homology)!<br />
• PX! *!<br />
• Tub!<br />
• Proppin!<br />
• GPP34! *!<br />
• PPO! *!<br />
• ENTH!<br />
• Sec14!<br />
Discovered by <strong>Field</strong> lab!<br />
*!
Specific Binding Targets!<br />
Each Phosphoinositide Has Unique Functions!<br />
PI(3)P! PI(4)P! PI(5)P! PI(3,4)P2! PI(3,5)P2! PI(4,5)P2! PI(3,4,5)P3!<br />
EEA1-<br />
FYVE!<br />
p40phox!<br />
-PX!<br />
*!<br />
*!<br />
OSBP-<br />
PH!<br />
FAPP1-<br />
PH!<br />
GOLPH3<br />
-GPP34!<br />
None<br />
known! TAPP1-<br />
PH!<br />
*!<br />
p47phox!<br />
-PX!<br />
(AKT-<br />
PH)!<br />
ATG18-!<br />
Proppin!<br />
PLCδ-<br />
PH!<br />
Tubby-!<br />
Tub!<br />
BTK-<br />
PH!<br />
GRP1-<br />
PH!<br />
(AKT-<br />
PH)!<br />
*!<br />
OGT-<br />
PPO!<br />
Discovered by <strong>Field</strong> lab!<br />
*!
PDK1!<br />
AKT (= PKB)!<br />
N! Ser/Thr Kinase! PH! C! N! PH! Ser/Thr Kinase! C!<br />
PDK1-PH!<br />
PA!<br />
PI!<br />
PI3P!<br />
PI4P!<br />
PI34P2!<br />
PI35P2!<br />
PI45P2!<br />
PI345P3!<br />
AKT!<br />
PA!<br />
PI!<br />
PI3P!<br />
PI4P!<br />
PI5P!<br />
PI34P2!<br />
PI35P2!<br />
PI45P2!<br />
PI345P3!<br />
<strong>Field</strong> lab data!
Phosphoinositides Exert Their Effects via<br />
Specific Binding Proteins!<br />
IGF-1<br />
Receptor!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1!Y! -P!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI-3-kinase!<br />
PDK-1!<br />
AKT!<br />
T!-P!<br />
S!
Phosphoinositides Exert Their Effects via<br />
Specific Binding Proteins!<br />
IGF-1<br />
Receptor!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1!Y! -P!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI-3-kinase!<br />
PDK-1!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
mTOR!<br />
TORC2!
Phosphoinositides Exert Their Effects via<br />
Specific Binding Proteins!<br />
IGF-1<br />
Receptor!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1!Y! -P!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI-3-kinase!<br />
FOXO!<br />
Transcription!<br />
GSK3!<br />
Glycogen!<br />
Synthesis!<br />
PDK-1!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
Tuberin!<br />
mTOR!<br />
TORC2!<br />
BAD!<br />
Protein! Anti-apoptotic!<br />
Synthesis!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
PDK-1!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
TORC1!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
TORC1!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
mTOR!<br />
mammalian target of Rapamycin!<br />
TORC1! TORC2!<br />
Rapamycin-sensitive! Rapamycin-resistant!<br />
Raptor!<br />
mTOR!<br />
mLST8/GβL!<br />
PRAS40!<br />
Rictor!<br />
mTOR!<br />
mLST8/GβL!<br />
Sin1!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Anabolic Pathway!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Anabolic Pathway!<br />
Inhibited by low energy!<br />
or by low amino acids!
AMPK!<br />
AMP!<br />
low<br />
energy!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
LKB1!<br />
P!<br />
AMPK!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Anabolic Pathway!<br />
Inhibited by low energy!<br />
or by low amino acids!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
RagA/C-GTP!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
amino acid<br />
starvation!<br />
Anabolic Pathway!
Tuberous Sclerosis!<br />
1 in 6000 births in the U.S.!<br />
• Hamartomas - benign tumors!<br />
• Kidney!<br />
• Skin!<br />
• Cardiac rhabdomyomas!<br />
• Brain cortical tumors!<br />
• Giant cell astrocytomas!<br />
Due to Mutation of TSC1 or TSC2!<br />
TSC1 encodes Hamartin!<br />
TSC2 encodes Tuberin!<br />
Hamartomas show LOH!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Peutz-Jeghers Syndrome!<br />
1 in 120,000 births!<br />
• Hamartomas of GI tract - benign polyp tumors!<br />
• Pigmented lesions of the lips and inner cheek!<br />
Inherited mutation of LKB1!<br />
Hamartomas have LOH!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Cowden Disease!<br />
PTEN is a Tumor Suppressor!<br />
Inherited Diseases Due to PTEN Heterozygocity!<br />
• Hamartomas!<br />
• skin, thyroid, breast,<br />
oral mucosa, intestine!<br />
• 30-50% breast cancer!<br />
• Thyroid carcinoma!<br />
Bannayan-Zonana Syndrome!<br />
Lhermite Duclose Syndrome!<br />
• Meningiomas! • Hamartomas!<br />
• Macrocephaly!<br />
• Glial tumors!<br />
Hamartomas have LOH!<br />
• Hamartomas!<br />
• Macrocephaly!<br />
• Retardation!<br />
• Sporadic cases of breast cancers, glioblastomas are often<br />
PTEN-deficient!<br />
• 50% of malignant prostate cancers are PTEN-deficient!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Tumor Suppressors!
PIK3CA encodes p110α!
PI3K mutations<br />
found in cancers!<br />
WT PI3K!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Tumor Suppressors!<br />
Oncogenes!
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
Ras!<br />
p85! p110!<br />
PI3K!<br />
PIK3CA (p110α)!<br />
PTEN!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
PDK-1!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
PTEN! PI(4,5)P2!<br />
Approximate Frequency of Mutations in Sporadic Cancers!<br />
Breast!<br />
30%!<br />
25%!<br />
Endometrial!<br />
25%!<br />
50%!<br />
Colon!<br />
15%!<br />
40%!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Oncogenes!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Tumor Suppressors!<br />
Oncogenes!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Can we shut this off?!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
RAPAMYCIN (SIROLIMUS)!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
RAPAMYCIN (SIROLIMUS)!<br />
Tumor Suppressors!
Sirolimus = rapamycin!<br />
Rapamycin analogs!<br />
Temsirolimus = CCI-779 = Torisel (Wyeth) !<br />
Everolimus = RAD001 = Certican = Afinitor (Novartis)!<br />
Ridaforolimus = Deforolimus = AP23573 = MK-8669 (Ariad/Merck)!
Everolimus!<br />
for TSC!<br />
Before! After 3 months!
Efficacy in Endometrial Cancer! Efficacy in Bone and Soft Tissue Sarcomas!<br />
Efficacy in Breast Cancer!<br />
Efficacy in Relapsed Hodgkins Lymphoma!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
RAPAMYCIN (SIROLIMUS)!
Allosteric TORC1 (mTOR) inhibitors!<br />
Sirolimus = rapamycin!<br />
Rapamycin analogs!<br />
Temsirolimus = CCI-779 = Torisel (Wyeth) !<br />
Everolimus = RAD001 = Certican = Afinitor (Novartis)!<br />
Ridaforolimus = Deforolimus = AP23573 = MK-8669 (Ariad/Merck)!<br />
mTOR kinase inhibitors (catalytic site)!<br />
Dozen or so in development, many in Phase I/II trials already!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
Kinase inhibitors!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PDK-1!<br />
AKT!<br />
PI3K! WORTMANNIN !<br />
or LY294002!<br />
mTOR!<br />
mTOR!<br />
PRAS40!<br />
P!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
Class I PI3K Is A Dimer: A Regulatory & Catalytic Subunit!<br />
Class IA - RTK!<br />
regulatory<br />
p85<br />
catalytic!<br />
p110!<br />
p85α<br />
p55α<br />
p50α<br />
p85β<br />
p55γ<br />
p110α<br />
p110β<br />
p110δ<br />
Class IB - GPCR!<br />
regulatory p87<br />
regulatory p101<br />
catalytic!<br />
p110!<br />
α<br />
β<br />
γ<br />
p110γ<br />
85 binding<br />
85 binding<br />
85 binding<br />
p87<br />
p101<br />
(Genes Run in Families)!<br />
SH3<br />
SH3<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
P<br />
RhoGAP<br />
P<br />
homology<br />
P<br />
P<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2 110 binding<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
SH2<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
Ras binding C2 PIK homology Catalytic domain<br />
p110β 85 binding Ras binding C2 PIK homology Catalytic domain<br />
P<br />
PIK3CA!
Some PI3K inhibitors!<br />
(3)-(12) were developed in<br />
the last 6 years !<br />
These, and many more,<br />
are currently in clinical<br />
trials!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
New Drugs!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!
PI3K-like<br />
Protein Kinases!<br />
mTOR!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
New Drugs!
Novartis: NVP-BEZ235!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
New Drugs!
AKT Inhibitors!<br />
Perifosine failed in a Phase III trial for Colorectal Cancer!<br />
Preliminary slight efficacy for Endometrial Cancer!
AMPK!<br />
Y!-P!<br />
Y!-P!<br />
IRS-1! Y! -P!<br />
P!<br />
AMPK!<br />
LKB1!<br />
S6K!<br />
ribosome S6!<br />
Ras!<br />
PI(4,5)P2! PI(3,4,5)P3!<br />
p85! p110!<br />
PI3K!<br />
mTOR!<br />
mTOR!<br />
PDK-1!<br />
PRAS40!<br />
P!<br />
AKT!<br />
S! -P!<br />
T! -P!<br />
P!<br />
P!<br />
tuberin!hamartin! tuberin!hamartin!<br />
rheb-GTP! rheb-GDP!<br />
rheb GEF!<br />
TORC1!<br />
4EBP1!<br />
CAP-dependent translation!<br />
PTEN! PI(4,5)P2!<br />
TORC2!<br />
mTOR!<br />
New Drugs!
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