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1.
Comput Struct Biotechnol J ; 20: 5607-5621, 2022.
Article in English | MEDLINE | ID: mdl-36284707

ABSTRACT

The oncogene PI3Kα and the tumor suppressor PTEN represent two antagonistic enzymatic activities that regulate the interconversion of the phosphoinositide lipids PI(4,5)P2 and PI(3,4,5)P3 in membranes. As such, they are defining components of phosphoinositide-based cellular signaling and membrane trafficking pathways that regulate cell survival, growth, and proliferation, and are often deregulated in cancer. In this review, we highlight aspects of PI3Kα and PTEN interplay at the intersection of signaling and membrane trafficking. We also discuss the mechanisms of PI3Kα- and PTEN- membrane interaction and catalytic activation, which are fundamental for our understanding of the structural and allosteric implications on signaling at the membrane interface and may aid current efforts in pharmacological targeting of these proteins.

2.
Schizophr Bull ; 48(5): 1136-1144, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35757972

ABSTRACT

BACKGROUND AND HYPOTHESIS: Schizophrenia is characterized by a complex interplay between genetic and environmental risk factors converging on prominent signaling pathways that orchestrate brain development. The Akt/GSK3ß/mTORC1 pathway has long been recognized as a point of convergence and etiological mechanism, but despite evidence suggesting its hypofunction, it is still not clear if this is already established during the first episode of psychosis (FEP). STUDY DESIGN: Here, we performed a systematic phosphorylation analysis of Akt, GSK3ß, and S6, a mTORC1 downstream target, in fresh peripheral blood mononuclear cells from drug-naive FEP patients and control subjects. STUDY RESULTS: Our results suggest 2 distinct signaling endophenotypes in FEP patients. GSK3ß hypofunction exhibits a promiscuous association with psychopathology, and it is normalized after treatment, whereas mTORC1 hypofunction represents a stable state. CONCLUSIONS: Our study provides novel insight on the peripheral hypofunction of the Akt/GSK3ß/mTORC1 pathway and highlights mTORC1 activity as a prominent integrator of altered peripheral immune and metabolic states in FEP patients.


Subject(s)
Glycogen Synthase Kinase 3 beta , Mechanistic Target of Rapamycin Complex 1 , Psychotic Disorders , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Proto-Oncogene Proteins c-akt/metabolism
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