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LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1

Lizcano, Jose M; Göransson, Olga LU ; Toth, Rachel; Deak, Maria; Morrice, Nick A; Boudeau, Jerome; Hawley, Simon A; Udd, Lina; Makela, Tomi P and Hardie, D Grahame, et al. (2004) In EMBO Journal 23(4). p.833-843
Abstract
We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases.... (More)
We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases. Activities of endogenous NUAK2, QIK, QSK, SIK, MARK1, MARK2/3 and MARK4 were markedly reduced in LKB1-deficient cells. Neither LKB1 activity nor that of AMPK-related kinases was stimulated by phenformin or AICAR, which activate AMPK. Our results show that LKB1 functions as a master upstream protein kinase, regulating AMPK-related kinases as well as AMPK. Between them, these kinases may mediate the physiological effects of LKB1, including its tumour suppressor function. (Less)
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published
subject
keywords
diabetes, PAR1/MARK kinase, cancer, cell polarity, TOF–TOF mass spectrometry, Peutz–Jeghers syndrome
in
EMBO Journal
volume
23
issue
4
pages
833 - 843
publisher
Oxford University Press
external identifiers
  • pmid:14976552
  • scopus:12144287284
ISSN
1460-2075
DOI
10.1038/sj.emboj.7600110
language
English
LU publication?
yes
id
0321f560-2bf8-461e-8718-6efb02059480 (old id 1129488)
date added to LUP
2008-06-16 16:01:01
date last changed
2017-12-10 04:39:24
@article{0321f560-2bf8-461e-8718-6efb02059480,
  abstract     = {We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases. Activities of endogenous NUAK2, QIK, QSK, SIK, MARK1, MARK2/3 and MARK4 were markedly reduced in LKB1-deficient cells. Neither LKB1 activity nor that of AMPK-related kinases was stimulated by phenformin or AICAR, which activate AMPK. Our results show that LKB1 functions as a master upstream protein kinase, regulating AMPK-related kinases as well as AMPK. Between them, these kinases may mediate the physiological effects of LKB1, including its tumour suppressor function.},
  author       = {Lizcano, Jose M and Göransson, Olga and Toth, Rachel and Deak, Maria and Morrice, Nick A and Boudeau, Jerome and Hawley, Simon A and Udd, Lina and Makela, Tomi P and Hardie, D Grahame and Alessi, Dario R},
  issn         = {1460-2075},
  keyword      = {diabetes,PAR1/MARK kinase,cancer,cell polarity,TOF–TOF mass spectrometry,Peutz–Jeghers syndrome},
  language     = {eng},
  number       = {4},
  pages        = {833--843},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1},
  url          = {http://dx.doi.org/10.1038/sj.emboj.7600110},
  volume       = {23},
  year         = {2004},
}