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LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1
- Lizcano, Jose M (author)
-
- Göransson, Olga (author)
- Lund University,Lunds universitet,Signaltransduktionsforskning,Forskargrupper vid Lunds universitet,Insulin Signal Transduction,Lund University Research Groups
- Toth, Rachel (author)
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- Deak, Maria (author)
- Morrice, Nick A (author)
- Boudeau, Jerome (author)
- Hawley, Simon A (author)
- Udd, Lina (author)
- Makela, Tomi P (author)
- Hardie, D Grahame (author)
- Alessi, Dario R (author)
- show less...
- (creator_code:org_t)
- 2004-02-19
- 2004
- English.
- In: EMBO Journal. - : Wiley. - 1460-2075 .- 0261-4189. ; 23:4, s. 833-843
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- diabetes
- PAR1/MARK kinase
- cancer
- cell polarity
- TOF–TOF mass spectrometry
- Peutz–Jeghers syndrome
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- art (subject category)
- ref (subject category)
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- Lizcano, Jose M
- Göransson, Olga
- Toth, Rachel
- Deak, Maria
- Morrice, Nick A
- Boudeau, Jerome
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- Hawley, Simon A
- Udd, Lina
- Makela, Tomi P
- Hardie, D Graham ...
- Alessi, Dario R
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- EMBO Journal
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