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Class II phosphatidylinositol 3-kinase-C2? is essential for Notch signaling by regulating the endocytosis of ?-secretase in endothelial cells.

ABSTRACT: The class II ?-isoform of phosphatidylinositol 3-kinase (PI3K-C2?) plays a crucial role in angiogenesis at least in part through participating in endocytosis and, thereby, endosomal signaling of several cell surface receptors including VEGF receptor-2 and TGF? receptor in vascular endothelial cells (ECs). The Notch signaling cascade regulates many cellular processes including cell proliferation, cell fate specification and differentiation. In the present study, we explored a role of PI3K-C2? in Delta-like 4 (Dll4)-induced Notch signaling in ECs. We found that knockdown of PI3K-C2? inhibited Dll4-induced generation of the signaling molecule Notch intracellular domain 1 (NICD1) and the expression of Notch1 target genes including HEY1, HEY2 and NOTCH3 in ECs but not in vascular smooth muscle cells. PI3K-C2? knockdown did not inhibit Dll4-induced endocytosis of cell surface Notch1. In contrast, PI3K-C2? knockdown as well as clathrin heavy chain knockdown impaired endocytosis of Notch1-cleaving protease, ?-secretase complex, with the accumulation of Notch1 at the perinuclear endolysosomes. Pharmacological blockage of ?-secretase also induced the intracellular accumulation of Notch1. Taken together, we conclude that PI3K-C2? is required for the clathrin-mediated endocytosis of ?-secretase complex, which allows for the cleavage of endocytosed Notch1 by ?-secretase complex at the endolysosomes to generate NICD1 in ECs.

SUBMITTER: Shimizu S

PROVIDER: S-EPMC7933152 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells.

Shimizu Shota S Yoshioka Kazuaki K Aki Sho S Takuwa Yoh Y

Scientific reports 20210304 1

The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) plays a crucial role in angiogenesis at least in part through participating in endocytosis and, thereby, endosomal signaling of several cell surface receptors including VEGF receptor-2 and TGFβ receptor in vascular endothelial cells (ECs). The Notch signaling cascade regulates many cellular processes including cell proliferation, cell fate specification and differentiation. In the present study, we explored a role of PI3K-C2α in ...[more]

PMID: 33664344

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Project description:Cholangiocarcinoma (CCA) mortality rates are increasing as a result of rising incidence and limited curative treatment(s) for patients with advanced disease. NOTCH pathway reactivation has been reported in biliary malignancies to conflicting degrees, hindering prioritization of key therapeutic targets within the network and identification of candidate responder patients for NOTCH-directed therapies. We analyzed genomic data from 341 patients with CCA and identified NOTCH1 significantly increased in a subgroup characterized by distinct stromal infiltration. Network-wide imbalance of the NOTCH pathway was seen in CCA, including correlation of NOTCH1 with NOTCH3 and NOTCH ligands. Given the diversity of observed NOTCH receptor engagement, ?-secretase modulation was rationalized as a therapeutic option. Indeed, subcutaneous transplantation of sensitive and resistant CCA cell lines pretreated with a ?-secretase inhibitor (GSi) cocktail demonstrated the antineoplastic effects of GSi in a subset of CCA and led to the development of a 225-gene responder signature. This signature was validated in an independent cohort of 119 patients. Further, this signature was enriched in liver tumors initiated by hydrodynamic injections of activated-NOTCH as compared with the AKT-RAS-driven tumors. Candidate GSi-responder patients were characterized by distinct transcriptomes overlapping with previous hepatobiliary metastasis and stemness, unique stromal properties, and dysfunctional intratumoral immune infiltration. Pan-cancer analysis identified 41.9% of cancer types to harbor prospective GSi-responder patients, which was adapted into a 20-gene GSi-sensitivity score metric capable of discriminating nanomolar versus micromolar sensitivity to a cell-permeable GSi (Z-LLNle-CHO) across 60 diverse tumor lines (area under the curve = 1). Conclusion: We have established a GSi-responder signature with evidence across several patient cohorts, as well as in vitro and in vivo models, to enable precision medicine application of NOTCH-directed therapy in CCA as well as prospectively across diverse malignancies.

Dataset Information

Class II phosphatidylinositol 3-kinase-C2? is essential for Notch signaling by regulating the endocytosis of ?-secretase in endothelial cells.

Publications

Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells.

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