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SUMMARY:Sensing of nutrients and energy by the AMP-activated protein kinas
 e
DTSTART:20170501T133000
DTEND:20170501T143000
DTSTAMP:20260916T230207Z
UID:1df062ad3110208c6233b9bc42311a2054d3550c26f8c6d6fb78eea1
CATEGORIES:Conferences - Seminars
DESCRIPTION:Grahame HARDIE University of Dundee\, UK\nSEMINAR SERIES :  T
 rends in Physiology and Metabolism (Bio-682)\n\nAbstract:\nAMP-activated p
 rotein kinase (AMPK) occurs as heterotrimeric complexes containing catalyt
 ic a subunits and regulatory b and g subunits. Genes encoding these subuni
 ts are found in the genomes of almost all eukaryotes\, suggesting that thi
 s is an ancient signalling pathway that arose during early eukaryotic evol
 ution. In mammalian cells\, increased ADP:ATP ratios (signifying a comprom
 ised cellular energy state) are amplified by adenylate kinase into even la
 rger increases in AMP:ATP ratio. Binding of AMP or ADP to one or more of t
 hree sites on the AMPK-g subunit promotes activation of AMPK by enhancing 
 phosphorylation of Thr172 (located within the activation loop of the a sub
 unit kinase domain) by the upstream kinase LKB1\, as well as by inhibiting
  Thr172 dephosphorylation. Binding of AMP\, but not ADP\, also causes a fu
 rther allosteric activation of phosphorylated AMPK. All three activating e
 ffects of AMP or ADP are antagonized by ATP binding\, so that AMPK is acti
 vated in a sensitive manner by falling cellular energy status. Once activa
 ted\, AMPK acts to restore energy homeostasis by switching on catabolic pa
 thways producing ATP\, while switching off ATP-consuming processes\, inclu
 ding cell growth and proliferation.\n     This energy-sensing role of 
 AMPK is well established\, and is now referred to as the canonical pathway
 . However\, it is becoming increasingly clear that there are also non-cano
 nical\, AMP/ADP-independent pathways by which this kinase can be activated
 . One example is the phosphorylation of Thr172 by the Ca2+-activated kinas
 e CaMKK2\, which is the mechanism by which some hormones and cytokines act
 ivate AMPK. Another that has recently emerged is the ability of AMPK to se
 nse glucose availability. It has been known for many years that AMPK is ac
 tivated by acute starvation of cells for glucose\, but it had been assumed
  that this occurs because the cells are dependent on glucose for catabolic
  production of ATP. However\, we have recently shown that\, as long as alt
 ernate carbon sources such as glutamine are present\, removing glucose fro
 m the medium of mammalian cells causes rapid AMPK activation\, yet does no
 t always increase cellular AMP:ATP or ADP:ATP ratios. Unlike the canonical
  mechanism\, this effect requires N-myristoylation of the AMPK-b subunits\
 , and is associated with translocation of AMPK to lysosomal membranes. Wor
 king with the group of Shengcai Lin at Xiamen University\, we have shown t
 hat AMPK\, and a complex between the adaptor protein AXIN and LKB1\, are r
 ecruited to the lysosome by binding to LAMTOR1. The latter\, a resident pr
 otein of the lysosomal membrane that associates with the vacuolar proton p
 ump (v-ATPase)\, is a component of the Ragulator complex also involved in 
 the regulation of the mechanistic target-of-rapamycin complex-1 (mTORC1). 
 Lin’s group has shown that inactivation of AMPK by glucose requires its 
 metabolism as far as fructose-1\,6-bisphosphate (FBP)\, the substrate of F
 BP aldolase and the first intermediate committed to glycolysis. Their resu
 lts suggest that a conformational change in aldolase in the absence of FBP
  causes it to dissociate from the v-ATPase\, perhaps allowing AXIN:LKB1 co
 mplex and AMPK to bind instead.\n     The AMPK ortholog in budding yea
 st (the SNF1 complex) is activated by glucose starvation and is required f
 or most responses to glucose starvation\, but it has always been puzzling 
 that it is not regulated by AMP in the same manner as mammalian AMPK. Intr
 iguingly\, however\, yeast aldolase has been shown to associate with the v
 -ATPase located on the yeast vacuole (equivalent to the lysosome)\, and th
 is interaction only occurs when glucose is present in the medium [Lu et al
  (2004) J Biol Chem 279:8732]. This suggests that some elements of the nov
 el glucose-sensing mechanism that we have discovered in mammalian cells ma
 y be conserved in budding yeast. Glucose sensing may in fact represent the
  ancestral role of AMPK\, with its energy-sensing role emerging later.\n 
LOCATION:SV 1717 https://plan.epfl.ch/?room==SV%201717
STATUS:CONFIRMED
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