Restraining PI3K: mTOR signalling goes back to the membrane.
The lipid kinase phosphoinositide 3-kinase (PI3K) is activated in response to various extracellular signals including peptide growth factors such as insulin and insulin-like growth factors (IGFs). Phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)] generated by PI3K is central to the diverse responses elicited by insulin, including glucose homeostasis, proliferation, survival and cell growth. The actions of lipid phosphatases have been considered to be the main means of attenuating PI3K signalling, whereby the principal 3-phosphatase - phosphatase and tensin homologue deleted on chromosome 10 (PTEN) - dephosphorylates PtdIns(3,4,5)P(3), reversing the action of PI3K. Recently, however, another pathway of regulation of PI3K has been identified in which activation of PI3K itself is prevented. This finding, together with earlier work, strongly suggests that a major form of negative feedback inhibition of PI3K results from activated growth signalling via mammalian target of rapamycin (mTOR) and the p70 S6 kinase (S6K) - a pathway that could have consequences for the development of type 2 diabetes and tuberous sclerosis complex.
Harrington
Laura S
LS
Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London, UK.
Findlay
Greg M
GM
Lamb
Richard F
RF
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013002:Somatomedins / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D005947:Glucose; D007328:Insulin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D011494:Protein Kinases; D013002:Somatomedins; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; C546842:MTOR protein, human; C494929:PTEN protein, human