Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.
Coordinated activities of protein kinases and phosphatases ensure phosphorylation homeostasis, which, when perturbed, can instigate diseases, including cancer. Yet, in contrast to kinases, much less is known about protein phosphatase functions and their interactions and complexes. Here, we used quantitative affinity proteomics to assay protein-protein interactions for 54 phosphatases distributed across the three major protein phosphatase families, with additional analysis of their 12 co-factors. We identified 838 high-confidence interactions, of which 631, to our knowledge, have not been reported before. We show that inhibiting the activity of phosphatases PP1 and PP2A by okadaic acid disrupts their specific interactions, supporting the potential of therapeutics that target these proteins. Additional analyses revealed candidate physical and functional interaction links to phosphatase-based regulation of several signaling pathways and to human cancer. Our study provides an initial glimpse of the protein interaction landscape of phosphatases and their functions in cellular regulation.
Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
Leena
L
Yadav
Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
Fitsum
F
Tamene
Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
Helka
H
Göös
Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
Audrey
A
van Drogen
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki 00014, Finland.
Riku
R
Katainen
Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
Ruedi
R
Aebersold
Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
Matthias
M
Gstaiger
Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland. Electronic address: markku.varjosalo@helsinki.fi.
Markku
M
Varjosalo
D006801:Humans; D013058:Mass Spectrometry; D009369:Neoplasms / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D020543:Proteome; D040901:Proteomics; D015398:Signal Transduction; D000078791:Tandem Affinity Purification
D020543:Proteome; D010749:Phosphoprotein Phosphatases
cancer; interactome; protein phosphatase; protein-protein interactions; quantitative proteomics