A subset of RAB proteins modulates PP2A phosphatase activity.
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.
Max Plank Institute for Biochemistry, Martinried, Munich (Germany).
Francesca
F
Sacco
Max Plank Institute for Biochemistry, Martinried, Munich (Germany).
Anna
A
Mattioni
Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Karsten
K
Boldt
Department DiBEST, University of Calabria, Rende, Italy.
Simona
S
Panni
Max Plank Institute for Biochemistry, Martinried, Munich (Germany).
Elena
E
Santonico
Max Plank Institute for Biochemistry, Martinried, Munich (Germany).
Luisa
L
Castagnoli
Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.|Research Unit for Protein Science, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.
Marius
M
Ueffing
Max Plank Institute for Biochemistry, Martinried, Munich (Germany).
Gianni
G
Cesareni
D001667:Binding, Competitive; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D040901:Proteomics; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
C517191:PPP2R1A protein, human; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; C079856:RAB9A protein, human; D020691:rab GTP-Binding Proteins