New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion

A Zagórska, M Deak, DG Campbell, S Banerjee… - Science …, 2010 - science.org
A Zagórska, M Deak, DG Campbell, S Banerjee, M Hirano, S Aizawa, AR Prescott, DR Alessi
Science signaling, 2010science.org
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-1β (PP1β) complex, through
conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1β. Phosphorylation of
Ser445, Ser472, and Ser910 of MYPT1 by NUAK1 promoted the interaction of MYPT1 with
14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment …
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-1β (PP1β) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1β. Phosphorylation of Ser445, Ser472, and Ser910 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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