New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion.
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-1beta (PP1beta) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1beta. 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.
Zagórska
Anna
A
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK. azagorska@salk.edu
Deak
Maria
M
Campbell
David G
DG
Banerjee
Sourav
S
Hirano
Mariko
M
Aizawa
Shinichi
S
Prescott
Alan R
AR
Alessi
Dario R
DR
D048948:14-3-3 Proteins / Q000378:metabolism; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D020816:Amino Acid Motifs; D024722:Cardiac Myosins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D006801:Humans; D018994:Myosin Light Chains / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000378:metabolism*
D048948:14-3-3 Proteins; D018994:Myosin Light Chains; D020033:Protein Isoforms; D011994:Recombinant Proteins; D012097:Repressor Proteins; C107184:myosin light chain 2; D011494:Protein Kinases; C470845:NUAK1 protein, human; C486061:NUAK2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D043263:Myosin-Light-Chain Phosphatase; D024722:Cardiac Myosins