BCH3042 Lecture Notes - Lecture 22: Phosphatidylinositol (3,4,5)-Trisphosphate, Phosphatidylinositol 4,5-Bisphosphate, Pleckstrin Homology Domain
Lecture 22 – PI3K/Akt Signalling And its Role in Cancer
PI(3,4,5)P3 Recruits PI(3,4,5)P3 binding effector proteins to transduce signalling
• Unstimulated/resting cell (G0 of cell cycle)
o Undetectable PI(3,4,5)P3 levels: requires RTK to activate
• Stimulated cell (G1-M phase)
o PI(3,4,5)P3 is transiently produced at plasma membrane
o PI(3,4,5)P3 effectors are recruited to plasma membrane by binding to
PI(3,4,5)P3 via PH domain
• P110 catalytic domain: contains kinase activity → facilitates phosphorylation
of PI(4,5)P2 to form PI(3,4,5)P3
• PH domains have been identified in >300 proteins
• Interaction of PIs with PH domains containing proteins is fundamental to
P13K signalling and cell homeostasis
• Importance of PI(3,4,5)P3 and PH domain Interactions
o X-linked agammaglobulinemia (XLA)
▪ Arises from mutation in PH domain containing Bruton tyrosine
kinase (BTK)
▪ Symptoms present at 2 months old
▪ Immune deficiency
• Reduced number of mature B cells
▪ Caused by mutations in BTK gene → no activation of PKC (no
release of calcium from ER)
o Mechanism
▪ BCR/antigen engagement activates PI3K
▪ B cells proliferate and mature via activation of PKC and
calcium
▪ Mutant BTK prevent PKC activation
Mechanism Underlying Phosphoinositide 3-kinase (PI3K)-dependent Akt activation
• AKT: major effector of PI3K signalling
• PI3K/Akt signalling pathway regulates cell proliferation, cell cycle regulation,
cell survival, protein translation, angiogenesis, cell migration and metabolism
• Activated downstream of RTK
• Akt was first identified as an oncogene transduced by the retrovirus Akt-8
from an AKR thyoma
o 3 types: Akt1, Akt2, Akt3
o Akt= Serine threonine kinase
• Steps of Activation
o (1) PH (Pleckstrin homology) domain of Akt
binds its catalytic domain
▪ Inactive conformation – absence of
stimulus
▪ Located in cytosol
o (2) Akt PH domain binds PI(3,4,5)P3
▪ Akt recruited from cytosol to plasma
membrane
▪ Conformational change
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Document Summary
Lecture 22 pi3k/akt signalling and its role in cancer. Pi(3,4,5)p3 via ph domain: p110 catalytic domain: contains kinase activity facilitates phosphorylation of pi(4,5)p2 to form pi(3,4,5)p3, ph domains have been identified in >300 proteins. Interaction of pis with ph domains containing proteins is fundamental to. Importance of pi(3,4,5)p3 and ph domain interactions: x-linked agammaglobulinemia (xla, arises from mutation in ph domain containing bruton tyrosine kinase (btk, symptoms present at 2 months old. Inactive conformation absence of stimulus: located in cytosol, (2) akt ph domain binds pi(3,4,5)p3, akt recruited from cytosol to plasma membrane, conformational change, (3) akt phosphorylated at thr308 (mediated by enzyme: pdk1) and. Ser473 (enzyme: mtorc2: conformational change in akt (active form, (4) active akt dissociates from membrane, cytosol/nucleus. Regulation of akt activity: enzyme: phlpp1 dephosphorylates akt at ser473 (antagonizes enzyme mtorc2, phlpp2 dephosphorylates akt at thr308 (antagonizes pdk1, often exhibit aberrant expression in cancer and diabetes.