Sun, 20 Jul 2008 21:40:14 BST CiteULike: neils amp-dependent http://www.citeulike.org/user/neils/tag/amp-dependent CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/neils/article/2860601 <i>Molecular cell, Vol. 30, No. 2. (25 April 2008), pp. 214-226.</i><br /><br />AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status. AMPK phosphorylation of raptor mediates a metabolic checkpoint. DM Gwinn DB Shackelford DF Egan MM Mihaylova A Mery DS Vasquez BE Turk RJ Shaw doi:10.1016/j.molcel.2008.03.003 Molecular cell, Vol. 30, No. 2. (25 April 2008), pp. 214-226. 2008-06-04T09:28:55-00:00 2008 Molecular cell 1097-4164 30 2 214 226 amp-dependent checkpoint kinase phosphorylation raptor http://www.citeulike.org/user/neils/article/2054426 <i>Biochem Biophys Res Commun, Vol. 347, No. 4. (Sep 2006), pp. 867-871.</i><br /><br />Brain selective kinase 2 (BRSK2) has been identified as a member of AMPK related kinases. LKB1 can phosphorylate the Thr174 of BRSK2, increasing its activity >50-fold. In this study, we identified cAMP-dependent protein kinase A (PKA) as another upstream kinase of BRSK2, which can phosphorylate BRSK2 at Thr260. The association between these two proteins was confirmed by GST pull-down. Furthermore, our study indicated that the kinase activity of BRSK2 can be increased through phosphorylation by PKA. BRSK2 is activated by cyclic AMP-dependent protein kinase A through phosphorylation at Thr260. Zekun Guo Wenwen Tang Jian Yuan Xinya Chen Bo Wan Xiuting Gu Kuntian Luo Yingli Wang Long Yu Biochem Biophys Res Commun, Vol. 347, No. 4. (Sep 2006), pp. 867-871. 2007-12-04T03:22:09-00:00 2006 Biochem Biophys Res Commun 347 4 867 871 activation alignment amino-acid amp-dependent article-predikin cyclic data enzyme kinase molecular phosphorylation protein protein-serine-threonine sequence threonine http://www.citeulike.org/user/neils/article/2054421 <i>Proc Natl Acad Sci U S A, Vol. 101, No. 32. (Aug 2004), pp. 11886-11890.</i><br /><br />Epithelial Na(+) channels mediate the transport of Na across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4 and Nedd4-2, with loss of this inhibition leading to hypertension. Here, we report that these channels are maintained in the active state by the G protein-coupled receptor kinase, Grk2, which has been previously implicated in the development of essential hypertension. We also show that Grk2 phosphorylates the C terminus of the channel beta subunit and renders the channels insensitive to inhibition by Nedd4-2. This mechanism has not been previously reported to regulate epithelial Na(+) channels and provides a potential explanation for the observed association of Grk2 overactivity with hypertension. Here, we report a G protein-coupled receptor kinase regulating a membrane protein other than a receptor and provide a paradigm for understanding how the interaction between membrane proteins and ubiquitin protein ligases is controlled. The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels. Anuwat Dinudom Andrew Fotia Robert Lefkowitz John Young Sharad Kumar David Cook Proc Natl Acad Sci U S A, Vol. 101, No. 32. (Aug 2004), pp. 11886-11890. 2007-12-04T03:22:09-00:00 2004 Proc Natl Acad Sci U S A 101 32 11886 11890 amp-dependent animal article-predikin beta-adrenergic biochemical cattle cell channel chemical cultured cyclic duct electrophysiology epithelial feedback g-protein-coupled hypertension kinase ligases male mice models phosphorylation protein receptor salivary sodium ubiquitin-protein