BCH3042 Lecture Notes - Lecture 21: Phosphatidylinositol (3,4,5)-Trisphosphate, Signal Transduction, Inositol
25 May 2018
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Lecture 21 – Phosphoinositides (PIs)
• 7 of PIs
o Act to regulate every aspect of cellular function: movement, death,
translation
o P13K: Often disregulated in cancers (hyperactivated)
o P10 – negatively regulates pathway – switches off
pathway
o AKT: major effector of which P13 signals within cell
Phosphatidylinositol is the backbone of PI3K signalling
• Phosphoinositides are non-structural lipids in cell membrane
• 2-8% of total cellular phospholipids
• Consist of inositol ring attached to glycerol backbone
o Ring can undergo reversible phosphorylation at one or
combination of positions (3’, 4’, 5’)
o Phosphorylated by kinase
• 3-position phosphorylation of inositol ring is mediated by
phosphoinositide 3-kinase (PI3K)
• 7 PI species
o Each play distinct role in regulation of cellular
processes: cell architecture, metabolism, insulin
signalling, membrane trafficking, signal transduction
• Two regulators of PI signalling
o Kinases: phosphorylate the inositol head group
▪ E.g. PI3-Kinase (PI3K)
o Phosphatases: de-phosphorylate the inositol head group
▪ E.g. PTEN (3-phosphatase)
▪ Signalling molecules are switched off by
phosphatases
• Each PI species plays an essential role in signal transduction
• PI signalling is a process of addition (kinase) and subtraction
(phosphatase) of phosphate groups
How do Phosphoinositides Signal?
• PIs don’t have intrinsic enzyme activity
• PIs bind effector proteins to regulate their conformation and subcellular
localisation
• Conformational changes upon PI binding can directly in/activate effectors or
expose consensus motifs for phosphorylation
Mechanism Underlying Phosphoinositide 3-kinase (P13K)-mediated production of
PI(3,4,5)P3
• Can be recognised by proteins with C2, PH or PX domains
• PI3K and its product PI(3,4,5)P3 are major components of phosphoinositide
signalling pathway that are dysregulated in cancer
o Major role: signal transduction
• How PI(3,4,5)P3 is synthesised
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