title: mTORC2 modulates feedback regulation of p38 MAPK activity via DUSP10/MKP5 to confer differential responses to PP242 in glioblastoma.
abstract: Dual-specificity phosphatases (DUSPs) dephosphorylate MAP kinases (MAPKs) resulting in their inactivation. Activation of MAPK signaling leads to enhanced DUSP expression, thus establishing feedback regulation of the MAPK pathway. The DUSPs are subject to regulation at the post-translational level via phosphorylation resulting in alterations of protein stability. Here we report that mTORC2 function leads to stabilization of the p38 MAPK phosphatase, DUSP10, thereby inhibiting p38 activity. We demonstrate that mTORC2 binds DUSP10 and phosphorylates DUSP10 on serine residues 224 and 230. These phosphorylation events block DUSP10 turnover resulting in inactivation of p38 signaling. We further show that insulin-stimulated PI3K/mTORC2 signaling regulates DUSP10 stability and p38 activity. Importantly, knockdown of DUSP10 or ectopic overexpression of nonphosphorylatable or phosphomimetic DUSP10 mutants was sufficient to confer differential mTOR kinase inhibitor responses to GBM cells in vitro and in murine xenografts. Finally, DUSP10 was shown to be overexpressed in a significant number of GBM patients. These data demonstrate the ability of the mTORC2 pathway to exert regulatory effects on the DUSP10/p38 feedback loop to control the cellular effects of mTOR kinase inhibitors in GBM and support the use of DUSP10 expression as a surrogate biomarker to predict responsiveness.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA ; Division of Hematology-Oncology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
authors.forename: Angelica
authors.initials: A
authors.lastname: Benavides-Serrato
authors.affiliation: Division of Hematology-Oncology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Anderson
authors.affiliation: Division of Hematology-Oncology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
authors.forename: Brent
authors.initials: B
authors.lastname: Holmes
authors.affiliation: Division of Hematology-Oncology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
authors.forename: Cheri
authors.initials: C
authors.lastname: Cloninger
authors.affiliation: Division of Hematology-Oncology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Artinian
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA ; Division of Hematology-Oncology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
authors.forename: Tariq
authors.initials: T
authors.lastname: Bashir
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA ; Jonnson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA ; Molecular Biology Institute, University of California, Los Angeles, CA, USA ; Division of Hematology-Oncology, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gera
keywords: DUSP; mTOR; p38 MAPK