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

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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
]
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.

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Polypeptides
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