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

Jose M. Lizcano, Olga Goransson, Rachel Toth, Maria Deak, Nick A. Morrice, Jerome Boudeau, Simon Hawley, Lina Udd, Tomi P. Makela, D. Grahame Hardie, Dario R. Alessi

    Research output: Contribution to journalArticlepeer-review

    976 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)833-843
    Number of pages11
    JournalThe EMBO Journal
    Volume23
    Issue number4
    DOIs
    Publication statusPublished - Feb 2004

    Keywords

    • Cancer
    • Cell polarity
    • Diabetes
    • PAR1/MARK kinase
    • Peutz–Jeghers syndrome
    • TOF–TOF mass spectrometry

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