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PMID: 14976552 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 23 ·No. 4 ·2004-02-25 ·Pages 833-43

Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Mäkelä TP, Hardie DG, Alessi DR

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.

MeSH Terms
AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases Adaptor Proteins, Vesicular Transport/genetics,metabolism Amino Acid Sequence Cell Line Enzyme Activation Fibroblasts/metabolism Humans Molecular Sequence Data Multienzyme Complexes/genetics,metabolism Mutation Peptides/metabolism Phosphorylation Protein Binding Protein Serine-Threonine Kinases/genetics,metabolism Protein Subunits/genetics,metabolism Substrate Specificity
Chemicals
Adaptor Proteins, Vesicular Transport Multienzyme Complexes Peptides Protein Subunits STRADA protein, human Protein Serine-Threonine Kinases STK11 protein, human AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Lizcano Jose M
MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
Göransson Olga
Toth Rachel
Deak Maria
Morrice Nick A
Boudeau Jérôme
Hawley Simon A
Udd Lina
Mäkelä Tomi P
Hardie D Grahame
Alessi Dario R
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600110
Published
2004-02-25
Epub
2004-00-19
Pages
833-43
Language
English
Region
England
NLM ID
8208664
PMCID
PMC381014
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7600110 PMC Full Text View journal details
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