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

Article Details


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

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

EMBO J. 2004 Feb 25;23(4):833-43. Epub 2004 Feb 19.

PubMed ID
14976552 [ View in PubMed

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.

DrugBank Data that Cites this Article

NameUniProt ID
5'-AMP-activated protein kinase catalytic subunit alpha-1Q13131Details
Serine/threonine-protein kinase SIK1P57059Details
Serine/threonine-protein kinase SIK3Q9Y2K2Details
Serine/threonine-protein kinase MARK1Q9P0L2Details
Serine/threonine-protein kinase MARK2Q7KZI7Details
MAP/microtubule affinity-regulating kinase 3P27448Details
MAP/microtubule affinity-regulating kinase 4Q96L34Details
Maternal embryonic leucine zipper kinaseQ14680Details
NUAK family SNF1-like kinase 1O60285Details
NUAK family SNF1-like kinase 2Q9H093Details
Serine/threonine-protein kinase SIK2Q9H0K1Details