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1.  AMPK connects energy stress to PIK3C3/VPS34 regulation 
Autophagy  2013;9(7):1110-1111.
The class III phosphatidylinositol (PtdIns)-3 kinase, PIK3C3/VPS34, forms multiple complexes and regulates a variety of cellular functions, especially in intracellular vesicle trafficking and autophagy. Even though PtdIns3P, the product of PIK3C3, is thought to be a critical membrane marker for the autophagosome, it is unclear how PIK3C3 is regulated in response to autophagy-inducing stimuli. A complexity of PIK3C3 biology is due in part to the existence of multiple complexes, of which the ATG14- or UVRAG-containing complexes play important roles in autophagy. We recently discovered differential regulation of distinct PIK3C3 complexes in response to energy starvation and showed a mechanism by which AMPK directly phosphorylates PIK3C3 and BECN1 to regulate non- and pro-autophagic PIK3C3 complexes, respectively.
doi:10.4161/auto.24877
PMCID: PMC3722323  PMID: 23669030
VPS34 complexes; AMPK; BECN1; ATG14; autophagy
2.  AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 
Nature cell biology  2011;13(2):132-141.
Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.
doi:10.1038/ncb2152
PMCID: PMC3987946  PMID: 21258367
3.  Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy 
Cell  2013;152(1-2):290-303.
Summary
Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the non-autophagy Vps34 complex by phosphorylating T163/S165 in Vps34, therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the pro-autophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy essential gene present only in pro-autophagy Vps 34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy.
doi:10.1016/j.cell.2012.12.016
PMCID: PMC3587159  PMID: 23332761
4.  ULK1 induces autophagy by phosphorylating Beclin-1 and activating Vps34 lipid kinase 
Nature cell biology  2013;15(7):10.1038/ncb2757.
Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Upon amino acid starvation or mTOR inhibition the activated ULK1 phosphorylates Beclin-1 on S14, thereby, enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 S14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in C. elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy specific VPS34 complex and autophagy induction.
doi:10.1038/ncb2757
PMCID: PMC3885611  PMID: 23685627
5.  The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR 
Autophagy  2011;7(6):645-646.
The serine/threonine kinase ULK1 is a mammalian homolog of Atg1, part of the Atg1 kinase complex, which is the most upstream component of the core autophagy machinery conserved from yeast to mammals. In budding yeast, activity of the Atg1 kinase complex is inhibited by TORC1 (target of rapamycin complex 1), but how the counterpart ULK1 complex in mammalian cells is regulated has been unknown. Our laboratories recently discovered that AMPK associates with, and directly phosphorylates, ULK1 on several sites and this modification is required for ULK1 activation after glucose deprivation. In contrast, when nutrients are plentiful, the mTORC1 complex phosphorylates ULK1, preventing its association and activation by AMPK. These studies have revealed a molecular mechanism of ULK1 regulation by nutrient signals via the actions of AMPK and mTORC1.
doi:10.4161/auto.7.6.15123
PMCID: PMC3359466  PMID: 21460621
autophagy; ULK1; AMPK; mTOR; 14-3-3

Results 1-5 (5)