Energy dependent regulation of mTOR by LKB1-AMPK (Homo sapiens)

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1, 3, 56, 177, 161014, 152, 8, 9, 11-1346, 17p-AMPK alpha AMPK alpha AMPK beta RhebGDP TSC1TSC2 TSC1p-S1387-TSC2 p-AMPK alpha AMPK beta LKB1STRADMO25 p-AMPK heterotrimerAMP AMPK heterotrimer High ATP concentrationcytosolAMPK heterotrimer p-AMPK heterotrimer RhebGTP p-AMPK heterotrimer AMPK beta AMPK gamma AMPK gamma AMPK alpha AMPK beta STRAD AMPK gamma AMPK gamma MO25 PRKAB1PRKAB1ATPPPM1APRKAG1 STK11STRADB PRKAG3 GTP p-T172-PRKAA2 ADPPRKAG3 PRKAB2 MO25PRKAB1CAB39L AMP p-AMPK heterotrimerAMPTSC1 PRKAG2 PRKAG2 TSC1 PRKAB2 PRKAG1 PRKAA1 RHEB p-S1387-TSC2 p-T172-PRKAA2 PiPRKAG1 ATPTSC2 AMPPRKAG1 PRKAB2 PRKAG2 p-S722,S792-RPTOR-1RhebGTPPRKAA1 ADPPRKAG3 RhebGDPPRKAG3 PRKAB1CAB39 GDP LKB1STRADMO25p-T174-PRKAA1STK11AMPK heterotrimerPRKAA2 ADPATPATPAMPK heterotrimerTSC1p-S1387-TSC2H2ORPTORTSC1TSC2p-T174-PRKAA1STRADA PRKAG2 PRKAB2 RHEB PRKAA2 p-AMPK heterotrimerPiSTRAD


Description

Upon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. If the AMP:ATP ratio rises, this activation is maintained and AMPK activates the TSC complex by phosphorylating TSC2. Active TSC activates the intrinsic GTPase activity of Rheb, resulting in GDP-loaded Rheb and

inhibition of mTOR pathway.

Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=380972

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Bibliography

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  1. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC.; ''The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress.''; PubMed Europe PMC Scholia
  2. Davies SP, Helps NR, Cohen PT, Hardie DG.; ''5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC.''; PubMed Europe PMC Scholia
  3. Winder WW, Hardie DG.; ''Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise.''; PubMed Europe PMC Scholia
  4. Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A, Schutkowski M, Prescott AR, Clevers HC, Alessi DR.; ''MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm.''; PubMed Europe PMC Scholia
  5. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ.; ''AMPK phosphorylation of raptor mediates a metabolic checkpoint.''; PubMed Europe PMC Scholia
  6. Inoki K, Li Y, Xu T, Guan KL.; ''Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.''; PubMed Europe PMC Scholia
  7. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D.; ''LKB1 is the upstream kinase in the AMP-activated protein kinase cascade.''; PubMed Europe PMC Scholia
  8. Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC.; ''Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD.''; PubMed Europe PMC Scholia
  9. Wojtaszewski JF, Nielsen P, Hansen BF, Richter EA, Kiens B.; ''Isoform-specific and exercise intensity-dependent activation of 5'-AMP-activated protein kinase in human skeletal muscle.''; PubMed Europe PMC Scholia
  10. Hardie DG.; ''AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.''; PubMed Europe PMC Scholia
  11. Inoki K, Zhu T, Guan KL.; ''TSC2 mediates cellular energy response to control cell growth and survival.''; PubMed Europe PMC Scholia
  12. Rubink DS, Winder WW.; ''Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase.''; PubMed Europe PMC Scholia
  13. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J.; ''Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.''; PubMed Europe PMC Scholia
  14. Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP.; ''The LKB1 tumor suppressor kinase in human disease.''; PubMed Europe PMC Scholia
  15. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP, Alessi DR, Hardie DG.; ''Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade.''; PubMed Europe PMC Scholia
  16. Guertin DA, Sabatini DM.; ''Defining the role of mTOR in cancer.''; PubMed Europe PMC Scholia
  17. Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D.; ''Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114693view16:17, 25 January 2021ReactomeTeamReactome version 75
113139view11:20, 2 November 2020ReactomeTeamReactome version 74
112370view15:30, 9 October 2020ReactomeTeamReactome version 73
101272view11:16, 1 November 2018ReactomeTeamreactome version 66
100810view20:46, 31 October 2018ReactomeTeamreactome version 65
100351view19:21, 31 October 2018ReactomeTeamreactome version 64
99896view16:04, 31 October 2018ReactomeTeamreactome version 63
99453view14:38, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99117view12:40, 31 October 2018ReactomeTeamreactome version 62
93976view13:49, 16 August 2017ReactomeTeamreactome version 61
93577view11:27, 9 August 2017ReactomeTeamreactome version 61
87439view13:38, 22 July 2016MkutmonOntology Term : 'mTOR signaling pathway' added !
87438view13:38, 22 July 2016MkutmonOntology Term : 'signaling pathway' added !
86682view09:24, 11 July 2016ReactomeTeamreactome version 56
83161view10:14, 18 November 2015ReactomeTeamVersion54
81517view13:03, 21 August 2015ReactomeTeamVersion53
76988view08:28, 17 July 2014ReactomeTeamFixed remaining interactions
76693view12:06, 16 July 2014ReactomeTeamFixed remaining interactions
76019view10:08, 11 June 2014ReactomeTeamRe-fixing comment source
75728view11:20, 10 June 2014ReactomeTeamReactome 48 Update
75078view14:02, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74725view08:48, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AMP MetaboliteCHEBI:16027 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
AMPK heterotrimerComplexREACT_18135 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
CAB39 ProteinQ9Y376 (Uniprot-TrEMBL)
CAB39L ProteinQ9H9S4 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
LKB1

STRAD

MO25		ComplexREACT_17994 (Reactome)
MO25ProteinREACT_17734 (Reactome)
PPM1AProteinP35813 (Uniprot-TrEMBL)
PRKAA1 ProteinQ13131 (Uniprot-TrEMBL)
PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
PRKAB1ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 ProteinQ9UGI9 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RHEB ProteinQ15382 (Uniprot-TrEMBL)
RPTORProteinQ8N122 (Uniprot-TrEMBL)
Rheb GDPComplexREACT_7464 (Reactome)
Rheb GTPComplexREACT_7765 (Reactome)
STK11ProteinQ15831 (Uniprot-TrEMBL)
STRADA ProteinQ7RTN6 (Uniprot-TrEMBL)
STRADB ProteinQ9C0K7 (Uniprot-TrEMBL)
STRADProteinREACT_17339 (Reactome)
TSC1 TSC2ComplexREACT_7850 (Reactome)
TSC1 p-S1387-TSC2ComplexREACT_21675 (Reactome)
TSC1 ProteinQ92574 (Uniprot-TrEMBL)
TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-AMPK heterotrimer AMPComplexREACT_21851 (Reactome)
p-AMPK heterotrimerComplexREACT_17720 (Reactome)
p-S1387-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S722,S792-RPTOR-1ProteinQ8N122-1 (Uniprot-TrEMBL)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T174-PRKAA1ProteinQ13131 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowREACT_11183 (Reactome)
ADPArrowREACT_21348 (Reactome)
ADPArrowREACT_21413 (Reactome)
AMPArrowREACT_11183 (Reactome)
AMPK heterotrimerArrowREACT_21418 (Reactome)
AMPK heterotrimerREACT_11183 (Reactome)
AMPREACT_21293 (Reactome)
ATPREACT_11183 (Reactome)
ATPREACT_21348 (Reactome)
ATPREACT_21413 (Reactome)
ATPTBarREACT_11183 (Reactome)
H2OREACT_21418 (Reactome)
LKB1

STRAD

MO25		mim-catalysisREACT_11183 (Reactome)
MO25REACT_21345 (Reactome)
PPM1Amim-catalysisREACT_21418 (Reactome)
PiArrowREACT_21261 (Reactome)
PiArrowREACT_21418 (Reactome)
REACT_11183 (Reactome) The cytosolic AMPK complex is activated by phosphorylation. LKB1 phosphorylates AMPK heterotrimer on Thr174 of the alpha 1 subunit (or Thr172 on alpha 2 subunit) leading to activation of AMPK (if cellular AMP/ATP ratio is high) (Hawley SA et al, 2003; Woods A et al, 2003; Shaw RJ et al, 2004). Signals leading to this phosphorylation event can be mediated by exercise, leptin and adiponectin, the hypothalamic-sympathetic nervous system (SNS), and alpha adrenergic receptors, as demonstrated in studies of rat and human skeletal muscle (Minoksohi et al, 2002, Kahn et al, 2005). The details of AMPK activation in response to these stimuli will be annotated in the future. Nuclear AMPK may well be a substrate for LKB1 but, to date, there is no clear evidence for this.
REACT_21261 (Reactome) TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of a small G-protein Rheb. This results in the conversion of Rheb-GTP into Rheb-GDP and in the inhibition of the mTOR activation by GTP-bound Rheb (Inoki K et al, 2003; Tee AR et al, 2003).
REACT_21293 (Reactome) If AMP:ATP ratio rises, AMP (instead of ATP) is bound by the AMPK-gamma subunit, which inhibits the dephosphorylation of the AMPK-alpha subunit resulting in activation of AMPK. It is not clear, as of yet, whether AMP binds to unphosphorylated AMPK.
REACT_21345 (Reactome) Upon complex formation with STRAD and MO25, LKB1 (also known as serine/threonine kinase 11, STK11) is mostly cytosolic. LKB1 attains 20x activity towards the substrates belonging to the subfamily of AMPK-like kinases (5'AMP-activated protein kinases).
REACT_21348 (Reactome) Activated AMPK (phosphorylated on the alpha subunit and AMP bound) phosphorylates TSC2 on Ser1387, thereby activating the GAP activity of the TSC complex via an unknown mechanism.
REACT_21413 (Reactome) Activated AMPK (phosphorylated on Thr172/Thr174 and AMP bound) phosphorylates Raptor on Ser 722 and Ser 792. These phosphorylations are required for inhibition of mTORC1 activity in response to energy stress (Gwinn DM et al, 2008).
REACT_21418 (Reactome) Normally under low AMP:ATP conditions, the active AMPK is dephosphorylated (possibly by PP2C), and thus inactivated.
RPTORREACT_21413 (Reactome)
Rheb GDPArrowREACT_21261 (Reactome)
STK11REACT_21345 (Reactome)
STRADREACT_21345 (Reactome)
TSC1 TSC2REACT_21348 (Reactome)
TSC1 p-S1387-TSC2ArrowREACT_21348 (Reactome)
TSC1 p-S1387-TSC2mim-catalysisREACT_21261 (Reactome)
p-AMPK heterotrimer AMPmim-catalysisREACT_21348 (Reactome)
p-AMPK heterotrimer AMPmim-catalysisREACT_21413 (Reactome)
p-AMPK heterotrimerArrowREACT_11183 (Reactome)
p-AMPK heterotrimerREACT_21293 (Reactome)
p-AMPK heterotrimerREACT_21418 (Reactome)
p-S722,S792-RPTOR-1ArrowREACT_21413 (Reactome)
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