Abstract
Protein phosphatase 2A (PP2A) is one of the most abundant serine–threonine phosphatases in mammalian cells. PP2A is a hetero-trimeric holoenzyme participating in a variety of physiological processes whose deregulation is often associated to cancer. The specificity and activity of this phosphatase is tightly modulated by a family of regulatory B subunits that dock the catalytic subunit to the substrates. Here we characterize a novel and unconventional molecular mechanism controlling the activity of the tumor suppressor PP2A. By applying a mass spectrometry-based interactomics approach, we identified novel PP2A interacting proteins. Unexpectedly we found that a significant number of RAB proteins associate with the PP2A scaffold subunit (PPP2R1A), but not with the catalytic subunit (PPP2CA). Such interactions occur in vitro and in vivo in specific subcellular compartments. Notably we demonstrated that one of these RAB proteins, RAB9, competes with the catalytic subunit PPP2CA in binding to PPP2R1A. This competitive association has an important role in controlling the PP2A catalytic activity, which is compromised in several solid tumors and leukemias.
Highlights
Protein phosphatases act in concert with kinases to fine-tune signaling events by modulating the level of phosphorylated serine, threonine and tyrosine residues[1,2]
Protein-protein interactions play a pivotal role in defining the function of phosphatase 2A (PP2A), one of the most abundant serine/threonine phosphatase implicated in cancer development
In this study we report a new molecular mechanism that modulates the activity of the PP2A phosphatase in specific compartments of the cervical cancer cell line HeLa
Summary
Protein phosphatases act in concert with kinases to fine-tune signaling events by modulating the level of phosphorylated serine, threonine and tyrosine residues[1,2]. Protein phosphatase 2A is the most abundant serine/threonine phosphatase in mammals[3], controlling key physiological processes, including proliferation, apoptosis, differentiation and cell migration[4]. Such broad functional specificity is mediated by the array of subunits that associate in a combinatorial fashion to form the functional PP2A holoenzyme[5]. We report that RAB8 and RAB9 proteins interact with the PP2A scaffold subunit, PPP2R1A, in a GTP independent manner. This interaction impairs the assembly of the PP2A holoenzyme, which is inactivated. Our results are consistent with a model whereby some specific members of the RAB family play a crucial role in selectively inhibiting the PP2A tumor suppressor in specific subcellular compartments
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