Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85alpha  Regulatory Subunit

doi:10.1128/MCB.20.21.8035-8046.2000

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Molecular and Cellular Biology, November 2000, p. 8035-8046, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85 $alpha$ Regulatory Subunit

Kohjiro Ueki, Petra Algenstaedt, Franck Mauvais-Jarvis, and C. Ronald Kahn^*

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215

Received 23 March 2000/Returned for modification 8 May 2000/Accepted 9 August 2000

Phosphoinositide (PI) 3-kinase is a key mediator of insulin-dependent metabolic actions, including stimulation of glucosetransport and glycogen synthesis. The gene for the p85 $alpha$ regulatorysubunit yields three splicing variants, p85 $alpha$ , AS53/p55 $alpha$ , and p50 $alpha$ .All three have (i) a C-terminal structure consisting of two Srchomology 2 domains flanking the p110 catalytic subunit-bindingdomain and (ii) a unique N-terminal region of 304, 34, and 6 aminoacids, respectively. To determine if these regulatory subunitsdiffer in their effects on enzyme activity and signal transductionfrom insulin receptor substrate (IRS) proteins under physiologicalconditions, we expressed each regulatory subunit in fully differentiatedL6 myotubes using adenovirus-mediated gene transfer with or withoutcoexpression of the p110 $alpha$ catalytic subunit. PI 3-kinase activityassociated with p50 $alpha$ was greater than that associated with p85 $alpha$ or AS53. Increasing the level of p85 $alpha$ or AS53, but not p50 $alpha$ , inhibitedboth phosphotyrosine-associated and p110-associated PI 3-kinaseactivities. Expression of a p85 $alpha$ mutant lacking the p110-bindingsite ( $Delta$ p85) also inhibited phosphotyrosine-associated PI 3-kinaseactivity but not p110-associated activity. Insulin stimulationof two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase(p70^S6K), was decreased in cells expressing p85 $alpha$ or AS53 but not in cellsexpressing p50 $alpha$ . Similar inhibition of PI 3-kinase, Akt, and p70^S6K was observed, even when p110 $alpha$ was coexpressed with p85 $alpha$ or AS53.Expression of p110 $alpha$ alone dramatically increased glucose transportbut decreased glycogen synthase activity. This effect was reducedwhen p110 $alpha$ was coexpressed with any of the three regulatory subunits.Thus, the three different isoforms of regulatory subunit can relaythe signal from IRS proteins to the p110 catalytic subunit withdifferent efficiencies. They also negatively modulate the PI 3-kinasecatalytic activity but to different extents, dependent on theunique N-terminal structure of each isoform. These data also suggestthe existence of a mechanism by which regulatory subunits modulatethe PI 3-kinase-mediated signals, independent of the kinase activity,possibly through subcellular localization of the catalytic subunitor interaction with additional signalingmolecules.

^* Corresponding author. Mailing address: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Phone: (617) 732-2635.Fax: (617) 732-2593. E-mail: c.ronald.kahn{at}joslin.harvard.edu.

Molecular and Cellular Biology, November 2000, p. 8035-8046, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85 Regulatory Subunit

Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85 $alpha$ Regulatory Subunit