Anna ZagÃÂ_rska, a PhD student working in Dario Alessi's lab, has published a paper describing a new pathway by which the LKB1 tumour suppressor might regulate cell adhesion and polarity. Anna discovered that the key regulator of this pathway is an LKB1 activated protein kinase termed NUAK1. Anna observed that the NUAK1 kinase interacts with the myosin phosphatase complex by virtue of its ability to directly bind to the PP1 catalytic subunit via three highly conserved GILK motifs. Anna found that upon stimuli that induce cell detachment, NUAK1 phosphorylates the MYPT1 regulatory subunit of the myosin phosphatase complex, promoting interaction with 14-3-3 isoforms and thereby inhibiting myosin phosphatase complex activity. This enhances phosphorylation of myosin light chain, thereby leading to activation of crucial non-muscle myosin motor proteins that play vital roles in regulating the cytoskeleton as well as cell adhesion and polarity. Anna was able to validate and confirm the importance of her findings using LKB1 and NUAK1 knock-out cell lines (kindly provided by Mariko Hirano and Shinichi Aizawa, Kobe, Japan) as well as a NUAK1 inhibitor (BX795). Using these reagents Anna demonstrated that loss of the LKB1-NUAK1 pathway markedly enhanced cell adhesion and impaired cell detachment.
Anna's data indicate NUAK1 plays a major role in controlling cell adhesion and functions as a regulator of myosin phosphatase complexes. These findings also suggest that the LKB1 tumour suppressor influences the phosphorylation of targets not only through the AMPK family of kinases but also by controlling phosphatase complexes. These results define a new function for LKB1 in decreasing cell adhesion through inhibition of myosin phosphatase activity and indicate that NUAK1 may contribute to tumor invasion by activating cytoskeletal motor proteins and thereby promoting cell detachment.
A dramatic picture of a NUAK1 deficient fibroblast taken by Alan Prescott was selected as the cover of this week's science signalling (click here)
This study was also of particular interest to Dario Alessi, as his first project as a postdoc in 1991 in Philip Cohen's lab in Dundee was to purify the myosin phosphatase complex from Chicken Gizzard. After several years work in the cold room Dario purified and identified peptides that belonged to the myosin phosphatase complex that enabled the cloning of the different subunits of this enzyme including MYPT1. Click here to see Dario's original paper.
Dario then decided to work on protein kinases rather than phosphatases as he was unsure how interesting studying myosin phosphatase complexes would be. This was arguably a mistake as there has been an explosion of papers describing essential roles for regulation of myosin phosphatases in controlling cytoskeleton, cell structure and polarity. Myosin phosphatase complexes also function as master phosphatases acting on many substrates other than myosin light chain. Myosin phosphatases also regulated by phosphorylation by many trendy well-studied protein kinases such as Rock.
Anna is now undertaking postdoctoral research at the Molecular Neurobiology Laboratory, in Greg Lemke's lab at the Salk Institute, La Jolla, California.
To read a copy of Anna's paper that has made the cover story of Science Signaling click here
To hear a podcast about this work click here
Anna's data indicate NUAK1 plays a major role in controlling cell adhesion and functions as a regulator of myosin phosphatase complexes. These findings also suggest that the LKB1 tumour suppressor influences the phosphorylation of targets not only through the AMPK family of kinases but also by controlling phosphatase complexes. These results define a new function for LKB1 in decreasing cell adhesion through inhibition of myosin phosphatase activity and indicate that NUAK1 may contribute to tumor invasion by activating cytoskeletal motor proteins and thereby promoting cell detachment.
A dramatic picture of a NUAK1 deficient fibroblast taken by Alan Prescott was selected as the cover of this week's science signalling (click here)
This study was also of particular interest to Dario Alessi, as his first project as a postdoc in 1991 in Philip Cohen's lab in Dundee was to purify the myosin phosphatase complex from Chicken Gizzard. After several years work in the cold room Dario purified and identified peptides that belonged to the myosin phosphatase complex that enabled the cloning of the different subunits of this enzyme including MYPT1. Click here to see Dario's original paper.
Dario then decided to work on protein kinases rather than phosphatases as he was unsure how interesting studying myosin phosphatase complexes would be. This was arguably a mistake as there has been an explosion of papers describing essential roles for regulation of myosin phosphatases in controlling cytoskeleton, cell structure and polarity. Myosin phosphatase complexes also function as master phosphatases acting on many substrates other than myosin light chain. Myosin phosphatases also regulated by phosphorylation by many trendy well-studied protein kinases such as Rock.
Anna is now undertaking postdoctoral research at the Molecular Neurobiology Laboratory, in Greg Lemke's lab at the Salk Institute, La Jolla, California.
To read a copy of Anna's paper that has made the cover story of Science Signaling click here
To hear a podcast about this work click here