The phosphatidylinositol 3-kinase/akt cassette regulates purine nucleotide synthesis.
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is highly conserved throughout evolution and regulates cell size and survival and cell cycle progression. It regulates the latter by stimulating procession through G(1) and the G(1)/S phase transition. Entry into S phase requires an abundant supply of purine nucleotides, but the effect of the PI3K/Akt pathway on purine synthesis has not been studied. We now show that the PI3K/Akt cassette regulates both de novo and salvage purine nucleotide synthesis in insulin-responsive mouse mesenchymal cells. We found that serum and insulin stimulated de novo purine synthesis in serum-starved cells largely through PI3K/Akt signaling, and pharmacologic and genetic inhibition of PI3K/Akt reduced de novo synthesis by 75% in logarithmically growing cells. PI3K/Akt regulated early steps of de novo synthesis by modulating phosphoribosylpyrophosphate production by the non-oxidative pentose phosphate pathway and late steps by modulating activity of the bifunctional enzyme aminoimidazole-carboxamide ribonucleotide transformylase IMP cyclohydrolase, an enzyme not previously known to be regulated. The effects of PI3K/Akt on purine nucleotide salvage were likely through regulating phosphoribosylpyrophosphate availability. These studies define a new mechanism whereby the PI3K/Akt cassette functions as a master regulator of cellular metabolism and a key player in oncogenesis.
Wang
Wei
W
Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.
Fridman
Alla
A
Blackledge
William
W
Connelly
Stephen
S
Wilson
Ian A
IA
Pilz
Renate B
RB
Boss
Gerry R
GR
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D016193:G1 Phase / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D009709:Nucleotide Deaminases / Q000235:genetics / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011685:Purine Nucleotides / Q000096:biosynthesis* / Q000235:genetics; D016196:S Phase / Q000235:genetics; D015398:Signal Transduction
D007328:Insulin; D011685:Purine Nucleotides; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D009709:Nucleotide Deaminases; C021436:IMP cyclohydrolase