Modulation by insulin-like growth factor I of the phosphatase PTEN in astrocytes.
Characterization of intracellular pathways underlying the pleiotropic actions of insulin-like growth factor-I (IGF-I) on brain cells is incomplete. We analyzed IGF-I signalling on astrocytes through the canonical phosphatidylinositol 3-kinase (PI3K)/Akt pathway and focused on possible changes in PTEN, a phosphatase that modulates IGF-I signalling by inhibiting Akt activation and, in turn is positively regulated by PI3K. After exposure of astrocytes to IGF-I, PTEN mRNA and protein levels were reduced and its phosphatase activity diminished. Inhibition of PTEN involved activation of a PI3K/protein kinase C (PKC) pathway that decreased in a proteasome-dependent step the levels of the transcription factor Egr-1, a key regulator of PTEN levels in astrocytes, causing decreased binding of Egr-1 to the PTEN promoter. Enhanced mitogenesis in PTEN siRNA-transduced astrocytes after IGF-I suggested that reduced PTEN may be a permissive factor for the mitogenic activity of IGF-I. Subsequent recovery of reduced PTEN required also activation by IGF-I of PI3K to recruit in this case protein kinase A (PKA) which stimulated Egr-1 levels and, consequently PTEN synthesis. Because basal levels of PTEN in astrocytes are also governed by PI3K, IGF-I appears to modulate PTEN in astrocytes by redirecting its homeostasic control through PI3K in a timed fashion.
Laboratory of Neuroendocrinology, Cajal Institute, CSIC, Madrid, Spain.
Silvia
S
Fernández
Miguel
M
García-García
Ignacio
I
Torres-Alemán
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D051059:PTEN Phosphohydrolase