Protein Phosphatase Interactome Given Its Due

    Called the yin and yang of protein phosphorylation and cell signaling, protein kinases and protein phosphatases haven’t exactly received equal treatment. Protein kinases have been stars of pathway analysis, whereas protein phosphatases have been patient understudies. Yet protein phosphatases may finally be stepping into the spotlight. New studies suggest that protein phosphatases are not just supporting players in signal transduction. Most recently, protein phosphatases grabbed the lead role in a systematic study of protein–protein interactions undertaken by a team of Finnish and Swiss Researchers.

    The research team, led by Markku Varjosalo, Ph.D., of the University of Helsinki, 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. “This study is a continuum of our almost decade-long effort to systematically dissect the molecular mechanisms behind the protein phosphorylation,” commented Dr. Varjosalo. “After our extensive analyses on protein kinases, the protein phosphatases were naturally to follow.”

    Details of the new study appeared March 15 in the journal Cell Systems in an article entitled “Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.” The article describes how the Finnish–Swiss team identified 838 high-confidence interactions. Of these 838 interactions, 631 appear to be newly discovered.

    “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,” the article’s authors wrote. “Additional analyses revealed candidate physical and functional interaction links to phosphatase-based regulation of several signaling pathways and to human cancer.”

    The article begins by noting that coordinated activities of protein kinases and protein phosphatases ensure phosphorylation homeostasis and amplitude of signaling response. It also points out that when phosphorylation homeostasis is perturbed, diseases such as cancer can result. Unlike with protein kinases, the current knowledge of protein phosphatase functions and especially on their formed interactions and complexes remains fragmentary.

    The current study constitutes a global quantitative interactomics analysis that covers half of the human protein phosphatome. It also derives and characterizes the molecular functions and pathways that the protein phosphatases connect via their stable or transient interactors. Furthermore, it reveals novel physical as well as functional links to phosphatase-based regulation of human cancer.

    “The protein phosphatases were too long thought to just be the negative counterpart of protein kinases, with promiscuous activity and low intrinsic substrate specificity,” concluded Dr. Varjosalo. “Recent studies such as ours, however, establish protein phosphatases as positive and essential regulators of signal transduction, with remarkable substrate specificity and coordinated activities. The phosphatases are also promising targets for therapeutic intervention in the treatment of various cancers.