New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion

Anna Zagorska; Maria Deak; David G. Campbell; Sourav Banerjee; Mariko Hirano; Shinichi Aizawa; Alan R. Prescott; Dario R. Alessi

doi:10.1126/scisignal.2000616

New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion

Anna Zagorska (Lead / Corresponding author), Maria Deak, David G. Campbell, Sourav Banerjee, Mariko Hirano, Shinichi Aizawa, Alan R. Prescott, Dario R. Alessi (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

144 Citations (Scopus)

Abstract

The AMPK-related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1. We found that NUAK1 interacts with several myosin phosphatases, including the myosin phosphatase targeting-1 (MYPT1)-protein phosphatase-1 beta (PP1 beta) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1b. Phosphorylation of Ser(445), Ser(472), and Ser(910) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment induced phosphorylation of endogenous MYPT1 by NUAK1, resulting in 14-3-3 binding to MYPT1 and enhanced phosphorylation of myosin light chain-2. Inhibition of the LKB1-NUAK1 pathway impaired cell detachment. Our data indicate that NUAK1 controls cell adhesion and functions as a regulator of myosin phosphatase complexes. Thus, LKB1 can influence the phosphorylation of targets not only through the AMPK family of kinases, but also by controlling phosphatase complexes.

Original language	English
Article number	ra25
Pages (from-to)	-
Number of pages	13
Journal	Science Signaling
Volume	3
Issue number	115
DOIs	https://doi.org/10.1126/scisignal.2000616
Publication status	Published - 30 Mar 2010

Keywords

ACTIVATED PROTEIN-KINASE
STRUCTURAL BASIS
REGULATORY SUBUNITS
SIGNALING PATHWAYS
CATALYTIC SUBUNIT
SKELETAL-MUSCLE
HUMAN CANCER
LKB1
AMPK
SUBSTRATE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion",

abstract = "The AMPK-related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1. We found that NUAK1 interacts with several myosin phosphatases, including the myosin phosphatase targeting-1 (MYPT1)-protein phosphatase-1 beta (PP1 beta) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1b. Phosphorylation of Ser(445), Ser(472), and Ser(910) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment induced phosphorylation of endogenous MYPT1 by NUAK1, resulting in 14-3-3 binding to MYPT1 and enhanced phosphorylation of myosin light chain-2. Inhibition of the LKB1-NUAK1 pathway impaired cell detachment. Our data indicate that NUAK1 controls cell adhesion and functions as a regulator of myosin phosphatase complexes. Thus, LKB1 can influence the phosphorylation of targets not only through the AMPK family of kinases, but also by controlling phosphatase complexes.",

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AU - Zagorska, Anna

AU - Deak, Maria

AU - Campbell, David G.

AU - Banerjee, Sourav

AU - Hirano, Mariko

AU - Aizawa, Shinichi

AU - Prescott, Alan R.

AU - Alessi, Dario R.

PY - 2010/3/30

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N2 - The AMPK-related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1. We found that NUAK1 interacts with several myosin phosphatases, including the myosin phosphatase targeting-1 (MYPT1)-protein phosphatase-1 beta (PP1 beta) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1b. Phosphorylation of Ser(445), Ser(472), and Ser(910) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment induced phosphorylation of endogenous MYPT1 by NUAK1, resulting in 14-3-3 binding to MYPT1 and enhanced phosphorylation of myosin light chain-2. Inhibition of the LKB1-NUAK1 pathway impaired cell detachment. Our data indicate that NUAK1 controls cell adhesion and functions as a regulator of myosin phosphatase complexes. Thus, LKB1 can influence the phosphorylation of targets not only through the AMPK family of kinases, but also by controlling phosphatase complexes.

AB - The AMPK-related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1. We found that NUAK1 interacts with several myosin phosphatases, including the myosin phosphatase targeting-1 (MYPT1)-protein phosphatase-1 beta (PP1 beta) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1b. Phosphorylation of Ser(445), Ser(472), and Ser(910) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment induced phosphorylation of endogenous MYPT1 by NUAK1, resulting in 14-3-3 binding to MYPT1 and enhanced phosphorylation of myosin light chain-2. Inhibition of the LKB1-NUAK1 pathway impaired cell detachment. Our data indicate that NUAK1 controls cell adhesion and functions as a regulator of myosin phosphatase complexes. Thus, LKB1 can influence the phosphorylation of targets not only through the AMPK family of kinases, but also by controlling phosphatase complexes.

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KW - SUBSTRATE

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New Roles for the LKB1-NUAK Pathway in Controlling Myosin Phosphatase Complexes and Cell Adhesion

Abstract

Keywords

UN SDGs

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