title: Mxi2 sustains ERK1/2 phosphorylation in the nucleus by preventing ERK1/2 binding to phosphatases.
abstract: ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPKs (mitogen-activated protein kinases) are tightly regulated by the cellular microenvironment in which they operate. Mxi2 is a p38α splice isoform capable of binding to ERK1/2 and ensuring their translocation to the nucleus. Therein Mxi2 sustains ERK1/2 phosphorylation levels and, as a consequence, ERK1/2 nuclear signals are enhanced. However, the molecular mechanisms underlying this process are still unclear. In the present study, we show that Mxi2 prevents nuclear but not cytoplasmic phosphatases from binding to and dephosphorylating ERK1/2, disclosing an unprecedented mechanism for the spatial regulation of ERK1/2 activation. We also demonstrate that the kinetics of ERK1/2 extranuclear signals can be significantly altered by artificially tethering Mxi2 to the cytoplasm. In this case, Mxi2 abolishes ERK1/2 inactivation by cytoplasmic phosphatases and potentiates ERK1/2 functions at this compartment. These results highlight Mxi2 as a key spatial regulator of ERK1/2 functions, playing a pivotal role in the balance between ERK1/2 nuclear and cytoplasmic signals.
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas - IDICAN - Universidad de Cantabria, Santander 39011, Cantabria, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Casar
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez
authors.forename: Gilad
authors.initials: G
authors.lastname: Gibor
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
authors.forename: Piero
authors.initials: P
authors.lastname: Crespo
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases