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

In English

Författare

  • Jose M Lizcano
  • Olga Göransson
  • Rachel Toth
  • Maria Deak
  • Nick A Morrice
  • Jerome Boudeau
  • Simon A Hawley
  • Lina Udd
  • Tomi P Makela
  • D Grahame Hardie
  • Dario R Alessi
Visa allt

Summary, in English

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.

Publiceringsår

2004

Språk

Engelska

Sidor

833-843

Publikation/Tidskrift/Serie

EMBO Journal

Volym

23

Issue

4

Dokumenttyp

Artikel i tidskrift

Förlag

Oxford University Press

Ämne

  • Biochemistry and Molecular Biology

Nyckelord

  • diabetes
  • PAR1/MARK kinase
  • cancer
  • cell polarity
  • TOF–TOF mass spectrometry
  • Peutz–Jeghers syndrome

Status

Published

Forskningsgrupp

  • Insulin Signal Transduction

ISBN/ISSN/Övrigt

  • ISSN: 1460-2075