mTORC2-mediated direct phosphorylation regulates YAP activity promoting glioblastoma growth and invasive characteristics
| Autor: | Sunil Kumar, Robert N. Nishimura, Jacquelyn T Saunders, Angelica Benavides-Serrato, Brent Holmes, Joseph Gera |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Mechanistic Target of Rapamycin Complex 2 Mice SCID Signal transduction Biology mTORC2 Mice Transactivation Cell Line Tumor Animals Humans Hippo Signaling Pathway Neoplasm Invasiveness Phosphorylation RC254-282 Original Research Hippo signaling pathway Brain Neoplasms Cell growth Neoplasms. Tumors. Oncology. Including cancer and carcinogens YAP-Signaling Proteins Xenograft Model Antitumor Assays Tumor Burden Cell biology Crosstalk (biology) Hippo signaling Female YAP Glioblastoma |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 9, Pp 951-965 (2021) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | The Hippo and mTOR signaling cascades are major regulators of cell growth and division. Aberrant regulation of these pathways has been demonstrated to contribute to gliomagenesis and result in enhanced glioblastoma proliferation and invasive characteristics. Several crosstalk mechanisms have been described between these two pathways, although a complete picture of these signaling interactions is lacking and is required for effective therapeutic targeting. Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. We show that mTORC2 activity enhances YAP transcriptional activity and the induction of YAP-dependent target gene expression while its ablation via genetic or pharmacological means has the opposite affects on YAP function. mTORC2 interacts with YAP via Sin1 and mutational analysis of serine 436 demonstrates that this phosphorylation event affects several properties of YAP leading to enhanced transactivation potential. Moreover, YAP serine 436 mutants display altered glioblastoma growth, migratory capacity and invasiveness both in vitro and in xenograft experiments. We further demonstrate that mTORC2 is able to regulate a Hippo pathway resistant allele of YAP suggesting that mTORC2 can regulate YAP independent of Hippo signaling. Correlative associations between the expression of these components in GBM patient samples also supported the presence of this signaling relationship. These results advance a direct mTORC2/YAP signaling axis driving GBM growth, motility and invasiveness. |
| Databáze: | OpenAIRE |
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