PI3-Kinase Signaling

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PI3-Kinase Signaling
Fruman, et al., 2000. PI3-kinases. From
Signaling networks and cell cycle control, Ed. S.
Gutkind, Human Press, NJ., pp. 247-266. Roymans,
D. Slegers, H. 2001. Phosphatidylinositol
3-kinases in tumor progression. Eur. J. Biochem.
268487-498. Stein, RC. 2001. Prospects for
phosphoinositide 3-kinase inhibition as a cancer
treatment. Endocrine-Rel. Can. 8237-248. Brazil,
DP Hemmings, B. 2001. Ten years of protein
kinase B signalling a hard akt to follow.
Trends Biochem. Sci. 26657-664. Testa, J.
Bellacosa, A. 2001. Akt plays a central role in
tumorigenesis. PNAS 9810983-10985. Chan, etal.,
1999. Akt/PKB and other D3 phosphoinositide-regula
ted kinases. Ann. Rv. Biochem. 68965-1014. Yamada
, K Araki, M. 2001. Tumor suppressor PTEN
modulator of cell signaling, growth, migration,
and apoptosis. J cell Sci. 1142375-2382. Maehama,
et al., 2001. PTEN and myotubularin novel
phosphoinositide phosphatases. Ann. Rev. Biochem.
70247-279. Simpson, L. Parsons, R. 2001. PTEN
Life as a tumor suppressor. Exp. Cell Res.
26429-41.
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Who's who of phosphoinositide signaling
PI Phosphoinositide PIC
Phosphoinositidase C PI3-Kinase (PI3K)
Phosphoinositide 3-kinase PtdIns (PtdI, PI)
Phosphatidylinositol PtdIns(3)P (PtInsP, PIP)
Phosphatidylinositol 3-phosphate
PtdIns(4,5)P2 (PI(4,5)P2, PIP2)
Phosphatidylinositol (4,5)-bis
phosphate PtdIns(3,4,5) P3 (PI(3,4,5)P3, PIP3)
Phosphatidylinositol (3,4,5)- phosphate Ins(1,
4)P2 (IP2) Inositol (1,4)
bisphosphate Ins(1,4,5)P3 (IP3) Inositol
(1,4,5) trisphosphate DAG
Diacylglycerol PLC Phospholipase C
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PI Kinases
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Inositol Lipid Metabolism
PtdIns (3,4,5)P
PtdIns (3,4)P
PtdIns3P
2
3
PI3K
PI3K
PtdIns (4,5)P
PtdIns
PtdIns4P
2
PLC
Blue arrows rate limiting, receptor regulated
reactions
Ins(1,4,5)P DAG
3
5
PI3-K Family
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Phospholipid Recognition and membrane targeting
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PI3K and PLC
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PH Domain

• PLC favors PIP2
• GRP1 , Btk selective for PIP3
• PKB, PDK1 binds both, favors PIP3

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PI-mediated regulation of cellular responses
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PI3-K Signaling
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PI3-K Inhibitors
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Akt/Protein Kinase B activation
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Central Role of Akt
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Akt family
Brazil Hemmings
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Akt activation
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Growth factor receptor signaling to Akt
Brazil Hemmings, 2001
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Akt activity in blocking apoptosis
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PTEN (Phosphatase and tensin homolog deleted on
chromosome ten)
Yamada Araki, 2001.
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PTEN in cell signaling
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PTEN has a N-terminal phosphatase domain and a
C-terminal C2 domain
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Domain Structure of PTEN
Simpson Parsons, 2001. Exp. Cell Res. 26429-41.
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Model of PTEN-I(1,3,4,5) P4 complex
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PTEN is pro-apoptotic
PTEN
Wort
PI3K
PIP3
Akt
Akt-P
p70s6K
Bcl-2
Bad-P
Fkhd-P
Fas
Cell survival
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