Fig. 4

Regulation of PTEN, a major regulator of the PI3K/AKT signalling pathway. Growth factors bind receptor tyrosine kinases (RTKs) on the extracellular cell membrane, which leads to the recruitment and binding of PI3K (directly or through adaptor proteins) to its cytoplasmic domain through its regulatory subunit (P85). Activated PI3K phosphorylates of PI(4,5)P2 to PI(3,4,5)P3, which occurs through its catalytic subunit (P110). The serine/threonine kinases Akt and PDK1 are recruited to the membrane after binding to the pleckstrin homology (PH) domain of PI(3,4,5)P3. PDK1 and mTORC2 phosphorylate and activate Akt, which phosphorylates a number of downstream protein targets with the overall effect of enhancing cell proliferation, metabolism and survival whilst inhibiting apoptosis. PTEN is a major negative regulator of PI3K/Akt signalling through its phosphoinositide phosphatase activity which acts to directly antagonise PI3K activity by dephosphorylating PI(3,4,5)P3 to PI(4,5)P2. PTEN abundance and activity is highly regulated through various complementary mechanisms working at the transcriptional, post-transcriptional and post-translational levels (modified from [14])