How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance.
The Akt signalling pathway plays vital roles in controlling cellular responses to insulin as well as in proliferation and survival. Inhibition of Akt signalling leads to insulin resistance and type 2 diabetes, whereas hyperactivation of Akt promotes tumorigenesis. In this study, we investigate how modest changes in the activity of the Akt signalling pathway, to an extent that might be achieved by drug treatment, would impact on insulin resistance and tumorigenesis. Using insulin-resistant PDK1(K465E/K465E) PH domain knock-in mice, we found that introducing the PTEN(+/-) mutation to slightly stimulate Akt restored normal insulin sensitivity. Introducing the PDK1(K465E/K465E) PH domain knock-in mutation into cancer-prone PTEN(+/-) mice, lowered Akt activity only by about 50%, but led to a delay in tumour onset of ∼4 months in a broad range of tumours. This was also accompanied by slower growth of B cell follicular lymphomas, as monitored by magnetic resonance imaging. Our findings imply that signal transduction inhibitors that lead to a modest reduction in Akt activity would not only delay onset of tumours possessing elevated phosphoinositide 3-kinase pathway activity but would also reduce the growth rate of developed tumours.
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Stephan
S
Wullschleger
Kei
K
Sakamoto
Lana
L
Johnstone
Suzanne
S
Duce
Stewart
S
Fleming
Dario R
DR
Alessi
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011230:Precancerous Conditions / Q000201:enzymology* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017433:Protein Structure, Secondary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects
D007328:Insulin; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase