Abstract
Energy depletion activates AMP-activated protein kinase (AMPK) and inhibits cell growth via TSC2-dependent suppression of mTORC1 signaling. Long term energy depletion also induces apoptosis by mechanisms that are not well understood to date. Here we show that AMPK, activated by energy depletion, inhibited cell survival by binding to and phosphorylating IRS-1 at Ser-794. Phosphorylation of IRS-1 at this site inhibited phosphatidylinositol 3-kinase/Akt signaling, suppressed the mitochondrial membrane potential, and promoted apoptosis. Of the treatments promoting energy depletion, glucose deprivation, hypoxia, and inhibition of ATP synthesis in the mitochondria stimulated phosphorylation of IRS-1 at Ser-794 via an LKB1/AMPK-dependent manner, whereas oxidative stress and 2-deoxyglucose stimulated phosphorylation at this site via a Ca2+/calmodulin-dependent protein kinase kinase beta/AMPK axis. These data define a novel pathway that cooperates with other adaptive mechanisms to formulate the cellular response to energy depletion.
Highlights
GTPase Rheb, an upstream activator of mTORC1 [1, 2]
IRS-1 Phosphorylation at Ser-794 in Response to Glucose Deprivation, Hypoxia, and Oxidative Stress Depends on the AMPK Catalytic Subunit ␣—To determine whether IRS-1 phosphorylation at Ser-794 in response to energy depletion is AMPKdependent we either overexpressed or knocked down the catalytic subunit of AMPK, and we examined the effects of these treatments on IRS-1 phosphorylation at this site
Ser-794 provides an entry into a novel and previously unsuspected mechanism by which glucose deprivation and hypoxia mediate their physiological effects via regulation of IRS-1-associated PI 3-kinase/Akt signaling
Summary
GTPase Rheb, an upstream activator of mTORC1 [1, 2]. Activation of TSC2 inhibits mTORC1 and limits energy consumption by down-regulating anabolic pathways such as protein synthesis [3, 4].
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