BCH3042 Lecture Notes - Lecture 23: Phosphatidylinositol (3,4,5)-Trisphosphate, Tumor Suppressor Gene, Protein Kinase B
25 May 2018
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Lecture 23 – PTEN and Cancer
Role PTEN Plays in Regulating PI3K/Akt
Signalling
• PTEN (enzyme): tumour suppressor gene
o Dephosphorylate both proteins
o Negatively regulates levels of
PIP(3,4,5) (dephosphorylates) to
modulate downstream Akt
dependent signalling
o Switches PI3K/Akt signalling off
o PTEN (phosphatase and tensin
homologue on chromosome 10)
▪ 3-phosphatase that
degrades PI(3,4,5)P3 at plasma membrane
▪ Less of PI(3,4,5)P3 at membrane to recruit and activate Akt
• PHLLP1/PHLLP2 directly dephosphorylates Akt to oppose mTORC2 and
PDK1
Mechanisms Leading to Amplified PI3K/Akt Signalling in Cancer
• PI3K/AKt signalling is amplified in cancer → drives tumour growth and
metastasis
• How?
o By promoting cell proliferation and survival, and inhibiting apoptosis
via forkhead, BAD, and mTORC1
• Why?
o Because PI3K/Akt signalling components are mutated in cancer
▪ Negative regulators are inactivated e.g. PTEN, PHLPP1/1
▪ Positive regulators are hyperactivated e.g. P13K, Akt
• Effect:
o PI(3,4,5)P3 is constantly produced
• (1) Upstream stimulation (RTKs) – constantly active → lead to amplification
of Akt signalling pathway
• (2) Indirectly via cross talk with Ras/MAPK
o Mutations in Ras → effect on activation
• (3) Intrinsically via mutations in PI3K/Akt pathway components
o Activating
o Inactivating
• Found in cancers: breast, endometrial, colorectal, cervical, skin
• Mutations in PI3K/AKT/PTEN are mechanisms of endocrine therapy
resistance
o Her2 receptor – drives development of breast cancer
▪ Amplification of Her2 leads to upregulation of P13K→ Akt→
mTOR
o P13K (or Akt) oncogenic mutation or PTEn deletion/inactivation
o Paracrine growth factor receptor
▪ Signalling → P13K activation
o Oncogenic mutations in PI3-Kinase
▪ % mutations identified in each domain of PI3-kinase (PIK3CA)
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