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PI3K/AKT signaling inhibits NOTCH1 lysosome‐mediated degradation
Author(s) -
Platonova Natalia,
Manzo Teresa,
Mirandola Leonardo,
Colombo Michela,
Calzavara Elisabetta,
Vigolo Emilia,
Cermisoni Greta Chiara,
De Simone Daria,
Garavelli Silvia,
Cecchinato Valentina,
Lazzari Elisa,
Neri Antonino,
Chiaramonte Raffaella
Publication year - 2015
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22264
Subject(s) - lysosome , degradation (telecommunications) , pi3k/akt/mtor pathway , microbiology and biotechnology , protein kinase b , chemistry , signal transduction , biology , computer science , biochemistry , telecommunications , enzyme
The pathways of NOTCH and PI3K/AKT are dysregulated in about 60% and 48% of T‐cell acute lymphoblastic leukemia (T‐ALL) patients, respectively. In this context, they interact and cooperate in controlling tumor cell biology. Here, we propose a novel mechanism by which the PI3K/AKT pathway regulates NOTCH1 in T‐ALL, starting from the evidence that the inhibition of PI3K/AKT signaling induced by treatment with LY294002 or transient transfection with a dominant negative AKT mutant downregulates NOTCH1 protein levels and activity, without affecting NOTCH1 transcription. We showed that the withdrawal of PI3K/AKT signaling was associated to NOTCH1 phosphorylation in tyrosine residues and monoubiquitination of NOTCH1 detected by Ubiquitin capture assay. Co‐immunoprecipitation assay and colocalization analysis further showed that the E3 ubiquitin ligase c‐Cbl interacts and monoubiquitinates NOTCH1, activating its lysosomal degradation. These results suggest that the degradation of NOTCH1 could represent a mechanism of control by which NOTCH1 receptors are actively removed from the cell surface. This mechanism is finely regulated by the PI3K/AKT pathway in physiological conditions. In pathological conditions characterized by PI3K/AKT hyperactivation, such as T‐ALL, the excessive AKT signaling could lead to NOTCH1 signaling dysregulation. Therefore, a therapeutic strategy directed to PI3K/AKT in T‐ALL could contemporaneously inhibit the dysregulated NOTCH1 signaling. © 2015 Wiley Periodicals, Inc.